Indole and Indazole Compounds that Activate AMPK

ABSTRACT

The present invention relates to indole and indazole compounds of Formula (I) that activate 5′ adenosine monophosphate-activated protein kinase (AMPK). The invention also encompasses pharmaceutical compositions containing these compounds and methods for treating or preventing diseases, conditions, or disorders ameliorated by activation of AMPK.

FIELD OF THE INVENTION

The present invention relates to indole and indazole compounds thatactivate 5′ adenosine monophosphate-activated protein kinase (AMPK),pharmaceutical compositions containing these compounds, and the use ofthese compounds for treating or preventing diseases, conditions, ordisorders ameliorated by activation of AMPK.

BACKGROUND

Diabetes is a major public health concern because of its increasingprevalence and associated health risks. The disease is characterized byhigh levels of blood glucose resulting from defects in insulinproduction, insulin action, or both. Two major forms of diabetes arerecognized, type I and type II. Type I diabetes develops when the body'simmune system destroys pancreatic beta cells, the only cells in the bodythat make the hormone insulin that regulates blood glucose. To survive,people with type 1 diabetes must have insulin delivered by injection ora pump. Type II diabetes accounts for about 90 to 95 percent of alldiagnosed cases of diabetes. Type II diabetes usually begins as insulinresistance, a disorder in which the cells do not use insulin properly.Key target tissues, including liver, muscle, and adipose tissue, areresistant to the effects of insulin in stimulating glucose and lipidmetabolism. As the need for insulin rises, the pancreas gradually losesits ability to produce insulin. Controlling type II diabetes withmedication is essential; otherwise it can progress into pancreaticbeta-cell failure requiring complete dependence on insulin.

Obesity increases the risk of type II diabetes as well as many otherhealth conditions including coronary heart disease, stroke, and highblood pressure. More than one-third of U.S. adults (over 72 millionpeople) and 17% of U.S. children are obese. During 1980-2008, obesityrates doubled for adults and tripled for children. During the pastseveral decades, obesity rates for all population groups—regardless ofage, sex, race, ethnicity, socioeconomic status, education level, orgeographic region—have increased markedly.

Research has identified the enzyme 5′ adenosine monophosphate-activatedprotein kinase (AMPK) as a regulator of cellular and whole-body energyhomeostasis. AMPK is activated by cellular stress resulting indownstream events that serve to conserve or generate ATP. AMPK iscomposed of three distinct subunits, each with multiple isoforms: thealpha subunit (alpha 1 or 2); the beta subunit (beta 1 or 2); and thegamma subunit (gamma 1, 2, or 3); for a total of twelve possibleheterotrimeric isoforms.

In the liver, activated AMPK phosphorylates a variety of substratesincluding 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase(Clarke, P. R. & Hardie, D. G., EMBO J 9, 2439-2446 (1990)) andacetyl-CoA carboxylase (Carling, D. et al. FEBS Letters 223, 217-222(1987)) which inhibits cholesterol biosynthesis and decreases fatty acidsynthesis, respectively. Therefore, activation of AMPK should lead todecreases in the levels of triglycerides and cholesterol. AMPK is alsothought to regulate plasma glucose levels by decreasing hepaticgluconeogenesis through downregulation of key gene products followingphosphorylation of CRTC2 (Koo S. H. et. Al., Nature 437, 1109-1111(2005)). In muscle and myocardial tissues, AMPK activates the transportactivity of glucose transporter 4 (GLUT4) increasing glucose uptake intocells thereby producing an additional avenue for decreasing plasmaglucose (Kurth-Kraczek, E. J. et. al., Diabetes 48, 1667-1671 (1999)).AMPK activation has also been shown to enhance mitochondrial biogenesisimproving fatty acid oxidation and decreasing circulating lipids(Merrill, G. M. et. al., Am. J. Physiol. 273, E1107-E1112 (1997)).Direct activation of AMPK using AICAR (5-aminoimidazole-4-carboxamideriboside) has been shown to lead to beneficial effects on severalmetabolic endpoints including improved glucose disposal, decreasedhepatic glucose output and decreases in plasma triglycerides and freefatty acids (Song, X. M. et. al., Diabetologia 45, 56-65 (2002);Bergeron, R. et. al., Diabetes 50, 1076-1082 (2001); Buhl, E. S. et.al., Diabetes 50, 12-17 (2001); Iglesias, M. A. et. al., Diabetes 51,2886-2894 (2002), Fogarty, S. & Hardie, D. G., Biochim et Biophys Acta1804, 581-591 (2010)). Because of AMPK's pluripotent effects oncarbohydrate, lipid, and cholesterol metabolism and biosynthesis, agentsthat activate AMPK are attractive therapeutic targets for treatingmetabolic syndrome disorders such as diabetes, obesity, anddyslipidemia.

Decreases in renal AMPK activation have been implicated in the etiologyof diseases of the kidney, including diabetic nephropathy, acute kidneyinjury (AKI), and polycystic kidney disease (PKD); activation of AMPKthrough hormonal (adiponectin) or pharmacological (AICAR) mechanisms hasbeen shown to be protective in rodent models of these diseases. Indiabetic nephropathy decreased AMPK activation in podocytes occurs earlyin the disease and is associated with increased expression of theNADPH-Oxidase protein Nox4 and increased proteinuria. These effects werereduced following administration of the AMPK activators AICAR,metformin, and Adiponectin (Lee, M J. et. al. American Journal ofPhysiology—Renal Physiology. 292. F617-F627 (2007); Sharma, K. et. al.Journal of Clinical Investigation. 118. 1645-1656. (2008)). Inischemia/reperfusion models of AKI the AMPK activators metformin andAICAR were shown to dose-dependently reduce subsequent proteinuria,oxidative tissue damage, and kidney macrophage infiltration (Lempiainen,J. et. al. British Journal of Pharmacology 166. 1905-1915 (2012);Seo-Mayer, P. W. et. al. American Journal of Physiology—RenalPhysiology, 301, F1346-F1357 (2011)). In two rodent models of PKD theAMPK activator metformin was shown to reduce renal cyst expansion(Takiar, V. et. al. PNAS 108, 2462-2467 (2011)). These studies suggest abroad benefit of AMPK activators in multiple renal diseases.

The compounds of the present invention activate AMPK and are, therefore,useful in treating metabolic disorders such as diabetes, obesity, anddyslipidemia as well as the renal diseases chronic kidney disease,diabetic nephropathy, acute kidney injury and polycystic kidney disease.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (I) that activate 5′adenosine monophosphate-activated protein kinase and are useful fortreating or preventing disorders ameliorated by activation of AMPK inmammals, particularly humans,

or a pharmaceutically acceptable salt thereof, wherein

X is N or CH;

R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C), —S(O₂)OR_(A), —S(O₂)NHC(O)R_(D),5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or 1H-tetrazol-5-yl;

R_(A) is H or (C₁-C₆)alkyl;

R_(B) and R_(C) are independently H, (C₁-C₆)alkyl, or —S(O₂)R_(D);

R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents that are independently(C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, or NR_(E)R_(F);

R_(E) and R_(F) are independently H or (C₁-C₆)alkyl;

R₂, R₃, and R₄ are independently H, (C₁-C₆)alkoxy, (C₁-C₆)alkyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl, mercapto, nitro,—NR_(G)R_(H) or (NR_(G)R_(H))carbonyl;

R_(G) and R_(H) are independently H, (C₁-C₆)alkyl, or(C₁-C₆)alkylcarbonyl;

R₅ is H or (C₁-C₆)alkyl;

L is a bond, O, S, NR_(A), (C₁-C₆)alkylene, (C₂-C₆)alkenylene, or(C₂-C₆)alkynylene;

A is phenyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 2,3-dihydrobenzofuranyl,2,3-dihydro-1H-indenyl, imidazolyl, pyrazinyl, pyrazolyl, pyridinyl,pyrimidinyl, or thiazolyl, wherein each is optionally substituted with1, 2, 3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, aryl, aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkyl,arylcarbonyl, aryloxy, carboxy, carboxy(C₁-C₆)alkoxy,carboxy(C₁-C₆)alkyl, cyano, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkylcarbonyl, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl,heteroaryloxy, (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocycle(C₁-C₆)alkyl, (C₃-C₇)heterocyclecarbonyl,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, (C₃-C₇)heterocycleoxy, hydroxy,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), (NR_(J)R_(K))carbonyl, —NR_(M)R_(N),—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the aryl, aryl(C₁-C₆)alkoxy,aryl(C₁-C₆)alkyl, arylcarbonyl, and aryloxy are optionally substitutedwith 1, 2, 3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 or 2 hydroxy groups; wherein the(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkylcarbonyl, and(C₃-C₈)cycloalkyloxy are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl, andheteroaryloxy, are optionally substituted with 1, 2, or 3 substituentsthat are independently (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, cyano,halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N), or(NR_(M)R_(N))carbonyl; and wherein the (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocycle(C₁-C₆)alkyl,(C₃-C₇)heterocyclocarbonyl, (C₃-C₇)heterocyclocarbonyl(C₁-C₆)alkyl, and(C₃-C₇)heterocyclooxy, are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkoxysulfonyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylthio, carboxy,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N),(NR_(M)R_(N))carbonyl, or oxo;

R_(J) and R_(K) are independently H or (C₁-C₆)alkyl; and

R_(M) and R_(N) are independently H, (C₁-C₆)alkyl, or(C₁-C₆)alkylcarbonyl; or R_(M) and R_(N) together with the nitrogen theyare attached to form a 3 to 8 membered ring;

provided that Formula (I) does not encompass5-(4-bromophenyl)-1H-indole-3-carboxamide;5-(2′,6′-dihydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-3-carboxamide; and5-(2′,6′-dimethoxy-[1,1]biphenyl]-4-yl)-1H-indole-3-carboxamide.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) and at least onepharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the present invention provides a method fortreating or preventing metabolic disorders in a mammal, particularly ahuman, where the metabolic disorder is ameliorated by activation of 5′adenosine monophosphate-activated protein kinase comprisingadministering to the mammal or human, in need of such treatment, atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing type II diabetes in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing obesity in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing dyslipidemia in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing renal diseases in a mammal, particularly a human,where the renal disease is ameliorated by activation of 5′ adenosinemonophosphate-activated protein kinase comprising administering to themammal or human, in need of such treatment, a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method fortreating or preventing chronic kidney disease in a mammal, particularlya human, comprising administering to the mammal or human, in need ofsuch treatment, a therapeutically effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing acute kidney injury in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing polycystic kidney disease in a mammal,particularly a human, comprising administering to the mammal or human,in need of such treatment, a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides uses for compounds ofFormula (I) for preparing, or for the manufacture of, a medicament fortreating metabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (I) for preparing, or for the manufacture of, a medicament fortreating or preventing type II diabetes in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (I) for preparing, or for the manufacture of, a medicament fortreating or preventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (I) for preparing, or for the manufacture of, a medicament fortreating or preventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (I) for preparing, or for the manufacture of, a medicament fortreating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (I) for preparing, or for the manufacture of, a medicament fortreating or preventing chronic kidney disease in a mammal, particularlya human.

In another aspect, the present invention provides uses for compounds ofFormula (I) for preparing, or for the manufacture of, a medicament fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (I) for preparing, or for the manufacture of, a medicament fortreating or preventing acute kidney injury in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (I) for preparing, or for the manufacture of, a medicament fortreating or preventing polycystic kidney disease in a mammal,particularly a human.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1. A. Podocyte apoptosis was measured following 48 hours in mediacontaining no glucose or 30 mM glucose with addition of vehicle, 1 mMAICAR, or Ex 1. Apoptosis was measured by quantifying using commercialcell death ELISA (Roche). B. Western blot analysis of total andphosphorylated AMPK and ACC in podocytes following 48 hour treatmentwith 30 mM glucose and vehicle, 1 mM AICAR, or Ex 1. C and D.Quantification of triplicate samples from western blots for thephopho/total AMPK and ACC ratio.

DETAILED DESCRIPTION OF THE INVENTION

In another embodiment, the present invention provides compounds ofFormula (I)

or a pharmaceutically acceptable salt thereof, wherein

X is N or CH;

L is a bond, O, S, NR_(A), (C₁-C₆)alkylene, (C₂-C₆)alkenylene, or(C₂-C₆)alkynylene;

A is

R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C), —S(O₂)OR_(A), —S(O₂)NHC(O)R_(D),5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or 1H-tetrazol-5-yl;

R_(A) is H or (C₁-C₆)alkyl;

R_(B) and R_(C) are independently H, (C₁-C₆)alkyl, or —S(O₂)R_(D);

R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenyl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents that are independently(C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, or NR_(E)R_(F);

R_(E) and R_(F) are independently H or (C₁-C₆)alkyl;

R₂, R₃, and R₄ are independently H, (C₁-C₆)alkoxy, (C₁-C₆)alkyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl, mercapto, nitro,—NR_(G)R_(H), or (NR_(G)R_(H))carbonyl;

R_(G) and R_(H) are independently H, (C₁-C₆)alkyl, or(C₁-C₆)alkylcarbonyl;

R₅ is H or (C₁-C₆)alkyl;

R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl;

R_(J) and R_(K) are independently H or (C₁-C₆)alkyl;

R₈ is H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, aryl, aryl(C₁-C₆)alkoxy,aryl(C₁-C₆)alkyl, arylcarbonyl, aryloxy, carboxy, carboxy(C₁-C₆)alkoxy,carboxy(C₁-C₆)alkyl, cyano, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkylcarbonyl, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl,heteroaryloxy, (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocycle(C₁-C₆)alkyl, (C₃-C₇)heterocyclecarbonyl,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, (C₃-C₇)heterocycleoxy, hydroxy,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), —NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the aryl, aryl(C₁-C₆)alkoxy,aryl(C₁-C₆)alkyl, arylcarbonyl, and aryloxy are optionally substitutedwith 1, 2, 3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 or 2 hydroxy groups; wherein the(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkylcarbonyl, and(C₃-C₈)cycloalkyloxy are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl, andheteroaryloxy, are optionally substituted with 1, 2, or 3 substituentsthat are independently (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, cyano,halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N), or(NR_(M)R_(N))carbonyl; and wherein the (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocycle(C₁-C₆)alkyl,(C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, and(C₃-C₇)heterocycleoxy, are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkoxysulfonyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylthio, carboxy,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N),(NR_(M)R_(N))carbonyl, or oxo; and

R_(M) and R_(N) are independently H, (C₁-C₆)alkyl, or(C₁-C₆)alkylcarbonyl; or R_(M) and R_(N) together with the nitrogen theyare attached to form a 3 to 8 membered ring;

provided that Formula (I) does not encompass5-(4-bromophenyl)-1H-indole-3-carboxamide;5-(2′,6′-dihydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-3-carboxamide; and5-(2′,6′-dimethoxy-[1,1]biphenyl]-4-yl)-1H-indole-3-carboxamide.

In another embodiment, the present invention provides compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, wherein X isN or CH; L is a bond or (C₂-C₆)alkynylene; A is

R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C), —S(O₂)OR_(A); R_(A) is H; R_(B) andR_(C) are independently H or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl; R₂, R₃, and R₄ are independently H, (C₁-C₆)alkyl, cyano, orhalogen; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₅ is H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, aryl, carboxy(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkyloxy,halo(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkoxy, (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,(C₃-C₇)heterocycleoxy, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N), (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the aryl is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy; whereinthe halo(C₁-C₆)alkyl is optionally with 1 hydroxy group; wherein the(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl, and(C₃-C₈)cycloalkyloxy are optionally substituted with 1 substituent thatis carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; andwherein the (C₃-C₇)heterocycle and (C₃-C₇)heterocycle(C₁-C₆)alkoxy areoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo; and R_(M) and R_(N) are independently H,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) and R_(N) together withthe nitrogen they are attached to form a 3 to 8 membered ring.

In another embodiment, the present invention provides compounds ofFormula (II)

or a pharmaceutically acceptable salt thereof, wherein X is N or CH; Lis a bond, O, S, NR_(A), (C₁-C₆)alkylene, (C₂-C₆)alkenylene, or(C₂-C₆)alkynylene; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C), —S(O₂)OR_(A),—S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, aryl, aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkyl,arylcarbonyl, aryloxy, carboxy, carboxy(C₁-C₆)alkoxy,carboxy(C₁-C₆)alkyl, cyano, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkylcarbonyl, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl,heteroaryloxy, (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocycle(C₁-C₆)alkyl, (C₃-C₇)heterocyclecarbonyl,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, (C₃-C₇)heterocycleoxy, hydroxy,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), —NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the aryl, aryl(C₁-C₆)alkoxy,aryl(C₁-C₆)alkyl, arylcarbonyl, and aryloxy are optionally substitutedwith 1, 2, 3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 or 2 hydroxy groups; wherein the(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkylcarbonyl, and(C₃-C₈)cycloalkyloxy are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl, andheteroaryloxy, are optionally substituted with 1, 2, or 3 substituentsthat are independently (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, cyano,halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N), or(NR_(M)R_(N))carbonyl; and wherein the (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocycle(C₁-C₆)alkyl,(C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, and(C₃-C₇)heterocycleoxy, are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkoxysulfonyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylthio, carboxy,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N),(NR_(M)R_(N))carbonyl, or oxo; and R_(M) and R_(N) are independently H,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; and R_(M) and R_(N) together withthe nitrogen they are attached to form a 3 to 8 membered ring; providedthat Formula (II) does not encompass5-(4-bromophenyl)-1H-indole-3-carboxamide;5-(2′,6′-dihydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-3-carboxamide; and5-(2′,6′-dimethoxy-[1,1]biphenyl]-4-yl)-1H-indole-3-carboxamide.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH or N; L is a bond; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C),—S(O₂)OR_(A), —S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,or 1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K) or (NR_(J)R_(K))carbonyl; R_(J) and R_(K) are independentlyH or (C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, carboxy(C₁-C₆)alkoxy,carboxy(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,mercapto, nitro, —NR_(M)R_(N), —NR_(M)R_(N)(C₁-C₆)alkoxy,—NR_(M)R_(N)(C₁-C₆)alkyl, (NR_(M)R_(N))carbonyl,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 or 2 hydroxy groups; and R_(M) and R_(N)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ areindependently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H,(C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is H,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉, and R₁₀ are H; and R₈ is hydroxy(C₁-C₆)alkoxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and R₁₀ are H; R₇ is H or(C₁-C₆)alkoxy; and R₈ is hydroxy(C₁-C₆)alkoxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and R₁₀ are H; R₇ is methoxy;and R₈ is hydroxy(C₁-C₆)alkoxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉, and R₁₀ are H; and R₈ is (C₁-C₆)alkoxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; and R₈ is(C₁-C₆)alkoxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and R₁₀ are H; R₇ is methoxy;and R₈ is (C₁-C₆)alkoxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ areindependently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H,(C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is H,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ areindependently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R_(A) is H; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independentlyH, (C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is H,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ areindependently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R_(A) is H; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independentlyH, (C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is H,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉, and R₁₀ are H; R₈ is(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆, R₉, and R₁₀ are H; R₇ is H or methoxy; R₈ is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II) or a pharmaceutically acceptable salt thereof, wherein X isCH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ areindependently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆, R₉, and R₁₀ are H; R₇ is H or methoxy; R₈ is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ areindependently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ areindependently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H,(C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ areindependently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H,(C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ areindependently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl,or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H,(C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen;R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H,(C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅is H; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy, halogen,hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆,R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy, halogen,hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ areindependently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆,R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ areindependently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independentlyH, (C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F,or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H,(C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀are independently H, (C₁-C₆)alkoxy, halogen, hydroxy, orhydroxy(C₁-C₆)alkyl; R₈ is (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl,—NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independentlyH, (C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F,or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are independently H,(C₁-C₆)alkoxy, halogen, hydroxy, or hydroxy(C₁-C₆)alkyl; R₈ is(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, carboxy(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, —NR_(M)R_(N)(C₁-C₆)alkoxy,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 hydroxy group; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH or N; L is a bond; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C),—S(O₂)OR_(A), —S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,or 1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl; R₈ is aryl, aryl(C₁-C₆)alkoxy,aryl(C₁-C₆)alkyl, arylcarbonyl, or aryloxy, wherein each is optionallysubstituted with 1, 2, 3, 4, or 5 substituents that are independently(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl,mercapto, nitro, —NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; and R_(M) andR_(N) are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; orR_(M) and R_(N) together with the nitrogen they are attached to form a 3to 8 membered ring; provided that Formula (II) does not encompass5-(4-bromophenyl)-1H-indole-3-carboxamide;5-(2′,6′-dihydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-3-carboxamide; and5-(2′,6′-dimethoxy-[1,1]biphenyl]-4-yl)-1H-indole-3-carboxamide.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₅ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₅ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₅ is aryl wherein the aryl isphenyl substituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₅is aryl wherein the aryl is phenyl substituted with 1 substituent thatis (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₅ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₅ is arylwherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ and R₅ are H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₅ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄, R₅, R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₅ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₅ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₅ is aryl wherein the aryl isphenyl substituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₅is aryl wherein the aryl is phenyl substituted with 1 substituent thatis (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₅ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₅ is arylwherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ isaryl wherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R_(A) is H; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R_(A) is H; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is arylwherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ areH; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituentthat is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl wherein the aryl isphenyl substituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ isaryl wherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R_(A) is H; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R_(A) is H; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is arylwherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ areH; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituentthat is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl wherein the aryl isphenyl substituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isaryl wherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H;R₈ is aryl wherein the aryl is phenyl substituted with 1 substituentthat is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isaryl wherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H;R₈ is aryl wherein the aryl is phenyl substituted with 1 substituentthat is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl isphenyl substituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈is aryl wherein the aryl is phenyl substituted with 1 substituent thatis (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is arylwherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl isphenyl substituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈is aryl wherein the aryl is phenyl substituted with 1 substituent thatis (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is arylwherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ isaryl wherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl,or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉and R₁₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl,or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl whereinthe aryl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxyor hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ areH; R₈ is aryl wherein the aryl is phenyl substituted with 1 substituentthat is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl wherein the aryl isphenyl substituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen;R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ andR₁₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen;R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl wherein the arylis phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈is aryl wherein the aryl is phenyl substituted with 1 substituent thatis (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ andR₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is arylwherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆,R₇, R₉, and R₁₀ are H; R₈ is aryl wherein the aryl is phenyl substitutedwith 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isaryl wherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H;R₈ is aryl wherein the aryl is phenyl substituted with 1 substituentthat is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is arylwherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆,R₇, R₉, and R₁₀ are H; R₈ is aryl wherein the aryl is phenyl substitutedwith 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl isphenyl substituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H;R₈ is aryl wherein the aryl is phenyl substituted with 1 substituentthat is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀are H; R₈ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is arylwherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F,or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy;R₉ and R₁₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F,or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl whereinthe aryl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxyor hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀are H; R₈ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is aryl wherein the aryl is phenylsubstituted with 1 substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is arylwherein the aryl is phenyl substituted with 1 substituent that is(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F, orCN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉and R₁₀ are H; R₈ is aryl wherein the aryl is phenyl substituted with 1substituent that is (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F, orCN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is aryl wherein thearyl is phenyl substituted with 1 substituent that is (C₁-C₆)alkoxy orhydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH or N; L is a bond; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C),—S(O₂)OR_(A), —S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,or 1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocycle(C₁-C₆)alkyl,(C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or(C₃-C₇)heterocycleoxy, wherein each is optionally substituted with 1, 2,or 3 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkoxysulfonyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylthio, carboxy,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N),(NR_(M)R_(N))carbonyl, or oxo; and R_(M) and R_(N) are independently H,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) and R_(N) together withthe nitrogen they are attached to form a 3 to 8 membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₅ is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₅ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₅is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₅ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle or(C₃-C₇)heterocycle(C₁-C₆)alkoxy, wherein the (C₃-C₇)heterocycle isazetidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl,pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl,wherein each is optionally substituted with 1 substituent that is(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylsulfonyl, hydroxy, hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is(C₃-C₇)heterocycle or (C₃-C₇)heterocycle(C₁-C₆)alkoxy, wherein the(C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl, piperazinyl,piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, ortriazolyl, wherein each is optionally substituted with 1 substituentthat is (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylsulfonyl, hydroxy, hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle wherein the(C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl, piperazinyl,piperidinyl, pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, ortriazolyl, wherein each is optionally substituted with 1 substituentthat is (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylsulfonyl, hydroxy, hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is(C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle(C₁-C₆)alkoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ is(C₃-C₇)heterocycle(C₁-C₆)alkoxy, wherein the (C₃-C₇)heterocycle isazetidinyl, morpholinyl, oxetanyl, piperazinyl, piperidinyl,pyrrolidinyl, tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl,wherein each is optionally substituted with 1 substituent that is(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylsulfonyl, hydroxy, hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₅ is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₅ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₅is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₅ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₅ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₅ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R_(A) is H; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ areH; R₈ is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R_(A) is H; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ areH; R₈ is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl,or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉and R₁₀ are H; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ areH; R₅ is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen;R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ andR₁₀ are H; R₅ is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈is (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ andR₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₅ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₅ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₅ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F,or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy;R₉ and R₁₀ are H; R₅ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, or (C₃-C₇)heterocycleoxy,wherein the (C₃-C₇)heterocycle is azetidinyl, morpholinyl, oxetanyl,piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuran,tetrahydro-2H-pyran, or triazolyl, wherein each is optionallysubstituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F, orCN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉and R₁₀ are H; R₈ is (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl,or (C₃-C₇)heterocycleoxy, wherein the (C₃-C₇)heterocycle is azetidinyl,morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyrrolidinyl,tetrahydrofuran, tetrahydro-2H-pyran, or triazolyl, wherein each isoptionally substituted with 1 substituent that is (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, hydroxy,hydroxy(C₁-C₆)alkyl, or oxo.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH or N; L is a bond; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C),—S(O₂)OR_(A), —S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,or 1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl; R₅ is heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl, orheteroaryloxy, wherein each is optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₅ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₅ is heteroaryl(C₁-C₆)alkoxy wherein the heteroaryl ispyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxywherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈is heteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein theheteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, R₉, andR₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein the heteroaryl ispyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxywherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₈is heteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₅ is heteroaryl(C₁-C₆)alkoxy wherein theheteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H; R₅ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₅ is heteroaryl(C₁-C₆)alkoxy wherein theheteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R_(A) is H; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₅ is heteroaryl(C₁-C₆)alkoxy wherein theheteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ areH; R₅ is heteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₅ is heteroaryl(C₁-C₆)alkoxy wherein theheteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R_(A) is H; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein theheteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ areH; R₈ is heteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxywherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein theheteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxywherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein theheteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein theheteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl,or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein the heteroaryl ispyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ areH; R₈ is heteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen;R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ andR₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein the heteroaryl ispyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈is heteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ andR₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxywherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein theheteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F,or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy;R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein the heteroarylis pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ isheteroaryl(C₁-C₆)alkoxy wherein the heteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein theheteroaryl is pyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F, orCN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉and R₁₀ are H; R₈ is heteroaryl(C₁-C₆)alkoxy wherein the heteroaryl ispyridinyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH or N; L is a bond; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C),—S(O₂)OR_(A), —S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,or 1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl; R₈ is (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkylcarbonyl, and (C₃-C₈)cycloalkyloxy wherein each isoptionally substituted with 1, 2, or 3 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl,mercapto, nitro, —NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; R_(M) and R_(N)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; or R_(M) andR_(N) together with the nitrogen they are attached to form a 3 to 8membered ring.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₉, and R₁₀are H; R₇ is H or methoxy; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₉, and R₁₀ are H; R₇ isH or methoxy; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy whereinthe (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and R₁₀ are H; R₇ is H ormethoxy; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the(C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or methoxy;R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl wherein the(C₃-C₈)cycloalkyl is cyclopropyl or cyclobutyl substituted withhydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or methoxy;R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and R₁₀ are H; R₇ is H ormethoxy; R₈ is (C₃-C₈)cycloalkyl wherein the (C₃-C₈)cycloalkyl iscyclopropyl or cyclobutyl substituted with hydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₅ is (C₃-C₈)cycloalkyl wherein the(C₃-C₈)cycloalkyl is cyclobutyl substituted with hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and R₁₀ are H; R₇ is H ormethoxy; R₅ is (C₃-C₈)cycloalkyl wherein the (C₃-C₈)cycloalkyl iscyclobutyl substituted with hydroxy.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₅ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₉, and R₁₀are H; R₇ is H or methoxy; R₅ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₅ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₉, and R₁₀ are H; R₇ isH or methoxy; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy whereinthe (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₉, and R₁₀ are H; R₇ is H ormethoxy; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the(C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R_(A) is H; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ areH; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the(C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl,or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy whereinthe (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) and R_(C) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy whereinthe (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond R₁ is —C(O)NR_(B)R_(C); R_(B) is H; R_(C) is—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independentlyH, F, or methoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl,cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F,or methoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl,or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy whereinthe (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ isH; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ areH; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the(C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen;R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉ andR₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the(C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅is H; R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the(C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —S(O₂)NHC(O)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃,or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4,or 5 substituents that are independently (C₁-C₆)alkoxy, (C₁-C₆)alkyl,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto,nitro, or NR_(E)R_(F); R_(E) and R_(F) are independently H or(C₁-C₆)alkyl; R₂ is H or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ andR₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H;R₆ and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor halogen; R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆and R₇ are independently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is Hor F; R₃ is methyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II) wherein X is N; L is a bond; R₁ is5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R₂ is H or F; R₃ is Cl, F, orCN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy whereinthe (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F,or CN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy;R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxywherein the (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areindependently H, F, or methoxy; R₉ and R₁₀ are H; R₈ is(C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each isoptionally substituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is methyl,cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, ormethoxy; R₉ and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or(C₃-C₈)cycloalkyloxy wherein the (C₃-C₈)cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, wherein each is optionallysubstituted with 1 substituent that is carboxy, hydroxy,hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl; and R_(M) and R_(N) areH.

In another embodiment, the present invention provides compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is 1H-tetrazol-5-yl; R₂ is H or F; R₃ is Cl, F, orCN; R₄ is H; R₅ is H; R₆ and R₇ are independently H, F, or methoxy; R₉and R₁₀ are H; R₈ is (C₃-C₈)cycloalkyl or (C₃-C₈)cycloalkyloxy whereinthe (C₃-C₈)cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, wherein each is optionally substituted with 1 substituentthat is carboxy, hydroxy, hydroxy(C₁-C₆)alkyl, or (NR_(M)R_(N))carbonyl;and R_(M) and R_(N) are H.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (II), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient, diluent, or carrier.

In another embodiment, the present invention provides a method fortreating or preventing metabolic disorders in a mammal, particularly ahuman, where the metabolic disorder is ameliorated by activation of 5′adenosine monophosphate-activated protein kinase comprisingadministering to the mammal or human, in need of such treatment, atherapeutically effective amount of a compound of Formula (II), or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing type II diabetes in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(II), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing obesity in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(II), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing dyslipidemia in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(II), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing renal diseases in a mammal, particularly a human,where the renal disease is ameliorated by activation of 5′ adenosinemonophosphate-activated protein kinase comprising administering to themammal or human, in need of such treatment, a therapeutically effectiveamount of a compound of Formula (II), or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method fortreating or preventing chronic kidney disease in a mammal, particularlya human, comprising administering to the mammal or human, in need ofsuch treatment, a therapeutically effective amount of a compound ofFormula (II), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(II), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing acute kidney injury in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(II), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing polycystic kidney disease in a mammal,particularly a human, comprising administering to the mammal or human,in need of such treatment, a therapeutically effective amount of acompound of Formula (II), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides uses for compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treatingmetabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing type II diabetes in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (II), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (II) for preparing, or for the manufacture of, a medicament fortreating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (II) for preparing, or for the manufacture of, a medicament fortreating or preventing chronic kidney disease in a mammal, particularlya human.

In another aspect, the present invention provides uses for compounds ofFormula (II) for preparing, or for the manufacture of, a medicament fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (II) for preparing, or for the manufacture of, a medicament fortreating or preventing acute kidney injury in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (II) for preparing, or for the manufacture of, a medicament fortreating or preventing polycystic kidney disease in a mammal,particularly a human.

In another embodiment, the present invention provides compounds ofFormula (III)

or a pharmaceutically acceptable salt thereof, wherein X is N or CH; Lis a bond, O, S, NR_(A), (C₁-C₆)alkylene, (C₂-C₆)alkenylene, or(C₂-C₆)alkynylene; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C), —S(O₂)OR_(A),—S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆, R₇, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, aryl, aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkyl,arylcarbonyl, aryloxy, carboxy, carboxy(C₁-C₆)alkoxy,carboxy(C₁-C₆)alkyl, cyano, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkylcarbonyl, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl,heteroaryloxy, (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocycle(C₁-C₆)alkyl, (C₃-C₇)heterocyclecarbonyl,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, (C₃-C₇)heterocycleoxy, hydroxy,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), —NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the aryl, aryl(C₁-C₆)alkoxy,aryl(C₁-C₆)alkyl, arylcarbonyl, and aryloxy are optionally substitutedwith 1, 2, 3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 or 2 hydroxy groups; wherein the(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkylcarbonyl, and(C₃-C₈)cycloalkyloxy are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl, andheteroaryloxy, are optionally substituted with 1, 2, or 3 substituentsthat are independently (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, cyano,halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N), or(NR_(M)R_(N))carbonyl; and wherein the (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocycle(C₁-C₆)alkyl,(C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, and(C₃-C₇)heterocycleoxy, are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkoxysulfonyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylthio, carboxy,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N),(NR_(M)R_(N))carbonyl, or oxo; and R_(M) and R_(N) are independently H,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; and R_(M) and R_(N) together withthe nitrogen they are attached to form a 3 to 8 membered ring.

In another embodiment, the present invention provides compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, and R₁₀are H; R₅ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, and R₁₀ are H; R₅ is(C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and R₁₀ are H; R₈ is(C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and R₁₀ are H; R₈ is(C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is morpholinyl.

In another embodiment, the present invention provides compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, and R₁₀are H; R₈ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, and R₁₀ are H; R₈ is(C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and R₁₀ are H; R₈ is(C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and R₁₀ are H; R₈ is(C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is morpholinyl.

In another embodiment, the present invention provides compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areH; R₁₀ is (C₁-C₆)alkoxy; R₈ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areH; R₁₀ is H or (C₁-C₆)alkoxy; R₈ is (C₃-C₇)heterocycle wherein the(C₃-C₇)heterocycle is pyrrolidinyl optionally substituted with(C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₇ areH; R₁₀ is H or (C₁-C₆)alkoxy; R₈ is (C₃-C₇)heterocycle wherein the(C₃-C₇)heterocycle is morpholinyl or pyrrolidinyl where the pyrrolidinylis optionally substituted with (C₁-C₆)alkoxy or hydroxy.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (III), or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the present invention provides a method fortreating or preventing metabolic disorders in a mammal, particularly ahuman, where the metabolic disorder is ameliorated by activation of 5′adenosine monophosphate-activated protein kinase comprisingadministering to the mammal or human, in need of such treatment, atherapeutically effective amount of a compound of Formula (III), or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing type II diabetes in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing obesity in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing dyslipidemia in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing renal diseases in a mammal, particularly a human,where the renal disease is ameliorated by activation of 5′ adenosinemonophosphate-activated protein kinase comprising administering to themammal or human, in need of such treatment, a therapeutically effectiveamount of a compound of Formula (III), or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method fortreating or preventing chronic kidney disease in a mammal, particularlya human, comprising administering to the mammal or human, in need ofsuch treatment, a therapeutically effective amount of a compound ofFormula (III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing acute kidney injury in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(III), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing polycystic kidney disease in a mammal,particularly a human, comprising administering to the mammal or human,in need of such treatment, a therapeutically effective amount of acompound of Formula (III), or a pharmaceutically acceptable saltthereof.

In another aspect, the present invention provides uses for compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treatingmetabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing type II diabetes in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (III), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (III) for preparing, or for the manufacture of, a medicament fortreating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (III) for preparing, or for the manufacture of, a medicament fortreating or preventing chronic kidney disease in a mammal, particularlya human.

In another aspect, the present invention provides uses for compounds ofFormula (III) for preparing, or for the manufacture of, a medicament fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (III) for preparing, or for the manufacture of, a medicament fortreating or preventing acute kidney injury in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (III) for preparing, or for the manufacture of, a medicament fortreating or preventing polycystic kidney disease in a mammal,particularly a human.

In another embodiment, the present invention provides compounds ofFormula (IV)

or a pharmaceutically acceptable salt thereof, wherein X is N or CH; Lis a bond, O, S,

NR_(A), (C₁-C₆)alkylene, (C₂-C₆)alkenylene, or (C₂-C₆)alkynylene; R₁ is—C(O)OR_(A), —C(O)NR_(B)R_(C), —S(O₂)OR_(A), —S(O₂)NHC(O)R_(D),5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or 1H-tetrazol-5-yl; R_(A) is Hor (C₁-C₆)alkyl; R_(B) and R_(C) are independently H, (C₁-C₆)alkyl, or—S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl, —CF₃, or phenyl, wherein the phenylis optionally substituted with 1, 2, 3, 4, or 5 substituents that areindependently (C₁-C₆)alkoxy, (C₁-C₆)alkyl, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, mercapto, nitro, orNR_(E)R_(F); R_(E) and R_(F) are independently H or (C₁-C₆)alkyl; R₂,R₃, and R₄ are independently H, (C₁-C₆)alkoxy, (C₁-C₆)alkyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl, mercapto, nitro,—NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H) areindependently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆ and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, aryl, aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkyl,arylcarbonyl, aryloxy, carboxy, carboxy(C₁-C₆)alkoxy,carboxy(C₁-C₆)alkyl, cyano, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkylcarbonyl, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl,heteroaryloxy, (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocycle(C₁-C₆)alkyl, (C₃-C₇)heterocyclecarbonyl,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, (C₃-C₇)heterocycleoxy, hydroxy,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), —NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the aryl, aryl(C₁-C₆)alkoxy,aryl(C₁-C₆)alkyl, arylcarbonyl, and aryloxy are optionally substitutedwith 1, 2, 3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 or 2 hydroxy groups; wherein the(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkylcarbonyl, and(C₃-C₈)cycloalkyloxy are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl, andheteroaryloxy, are optionally substituted with 1, 2, or 3 substituentsthat are independently (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, cyano,halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N), or(NR_(M)R_(N))carbonyl; and wherein the (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocycle(C₁-C₆)alkyl,(C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, and(C₃-C₇)heterocycleoxy, are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkoxysulfonyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylthio, carboxy,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N),(NR_(M)R_(N))carbonyl, or oxo; and R_(M) and R_(N) are independently H,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; and R_(M) and R_(N) together withthe nitrogen they are attached to form a 3 to 8 membered ring.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₁₀ areH; R₈ is —NR_(M)R_(N); and R_(M) and R_(N) are independently H or(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₁₀ are H; R₈ is—NR_(M)R_(N); and R_(M) and R_(N) are independently H or (C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₁₀ are H; R₈ is —NR_(M)R_(N);and R_(M) and R_(N) are independently H or (C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₁₀ are H;R₈ is —NR_(M)R_(N); and R_(M) and R_(N) are independently H or(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₁₀ are H; R₈ is—NR_(M)R_(N); and R_(M) and R_(N) are independently H or (C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₁₀ are H; R₈ is —NR_(M)R_(N);and R_(M) and R_(N) are independently H or (C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₁₀ areH; R₈ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is morpholinyl.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₁₀ are H;R₈ is (C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle.

In another embodiment, the present invention provides compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆ and R₁₀ are H; R₈ is(C₃-C₇)heterocycle wherein the (C₃-C₇)heterocycle is morpholinyl.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (IV), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient, diluent, or carrier.

In another embodiment, the present invention provides a method fortreating or preventing metabolic disorders in a mammal, particularly ahuman, where the metabolic disorder is ameliorated by activation of 5′adenosine monophosphate-activated protein kinase comprisingadministering to the mammal or human, in need of such treatment, atherapeutically effective amount of a compound of Formula (IV), or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing type II diabetes in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing obesity in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing dyslipidemia in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing renal diseases in a mammal, particularly a human,where the renal disease is ameliorated by activation of 5′ adenosinemonophosphate-activated protein kinase comprising administering to themammal or human, in need of such treatment, a therapeutically effectiveamount of a compound of Formula (IV), or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method fortreating or preventing chronic kidney disease in a mammal, particularlya human, comprising administering to the mammal or human, in need ofsuch treatment, a therapeutically effective amount of a compound ofFormula (IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing acute kidney injury in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(IV), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing polycystic kidney disease in a mammal,particularly a human, comprising administering to the mammal or human,in need of such treatment, a therapeutically effective amount of acompound of Formula (IV), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides uses for compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treatingmetabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing type II diabetes in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (IV), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (IV) for preparing, or for the manufacture of, a medicament fortreating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (IV) for preparing, or for the manufacture of, a medicament fortreating or preventing chronic kidney disease in a mammal, particularlya human.

In another aspect, the present invention provides uses for compounds ofFormula (IV) for preparing, or for the manufacture of, a medicament fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (IV) for preparing, or for the manufacture of, a medicament fortreating or preventing acute kidney injury in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (IV) for preparing, or for the manufacture of, a medicament fortreating or preventing polycystic kidney disease in a mammal,particularly a human.

In another embodiment, the present invention provides compounds ofFormula (V)

or a pharmaceutically acceptable salt thereof, wherein X is N or CH; Lis a bond, O, S, NR_(A), (C₁-C₆)alkylene, (C₂-C₆)alkenylene, or(C₂-C₆)alkynylene; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C), —S(O₂)OR_(A),—S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆ and R₉ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl; R₈ is H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, aryl, aryl(C₁-C₆)alkoxy, aryl(C₁-C₆)alkyl,arylcarbonyl, aryloxy, carboxy, carboxy(C₁-C₆)alkoxy,carboxy(C₁-C₆)alkyl, cyano, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy, (C₃-C₈)cycloalkyl(C₁-C₆)alkyl,(C₃-C₈)cycloalkylcarbonyl, (C₃-C₈)cycloalkyloxy, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl,heteroaryloxy, (C₃-C₇)heterocycle, (C₃-C₇)heterocycle(C₁-C₆)alkoxy,(C₃-C₇)heterocycle(C₁-C₆)alkyl, (C₃-C₇)heterocyclecarbonyl,(C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, (C₃-C₇)heterocycleoxy, hydroxy,hydroxy(C₁-C₆)alkoxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), —NR_(M)R_(N)(C₁-C₆)alkoxy, (NR_(M)R_(N))carbonyl,(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl, or(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy; wherein the aryl, aryl(C₁-C₆)alkoxy,aryl(C₁-C₆)alkyl, arylcarbonyl, and aryloxy are optionally substitutedwith 1, 2, 3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the halo(C₁-C₆)alkyl isoptionally substituted with 1 or 2 hydroxy groups; wherein the(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₆)alkoxy,(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, (C₃-C₈)cycloalkylcarbonyl, and(C₃-C₈)cycloalkyloxy are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(M)R_(N), or (NR_(M)R_(N))carbonyl; wherein the heteroaryl,heteroaryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkyl, heteroarylcarbonyl, andheteroaryloxy, are optionally substituted with 1, 2, or 3 substituentsthat are independently (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylthio, carboxy, cyano,halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N), or(NR_(M)R_(N))carbonyl; and wherein the (C₃-C₇)heterocycle,(C₃-C₇)heterocycle(C₁-C₆)alkoxy, (C₃-C₇)heterocycle(C₁-C₆)alkyl,(C₃-C₇)heterocyclecarbonyl, (C₃-C₇)heterocyclecarbonyl(C₁-C₆)alkyl, and(C₃-C₇)heterocycleoxy, are optionally substituted with 1, 2, or 3substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkoxysulfonyl, (C₁-C₆)alkyl,(C₁-C₆)alkylcarbonyl, (C₁-C₆)alkylsulfonyl, (C₁-C₆)alkylthio, carboxy,cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy,hydroxy(C₁-C₆)alkyl, mercapto, nitro, —NR_(M)R_(N),(NR_(M)R_(N))carbonyl, or oxo; and R_(M) and R_(N) are independently H,(C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; and R_(M) and R_(N) together withthe nitrogen they are attached to form a 3 to 8 membered ring.

In another embodiment, the present invention provides compounds ofFormula (V), or a pharmaceutically acceptable salt thereof, wherein X isCH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₉ are H;and R₈ is aryl wherein the aryl is phenyl.

In another embodiment, the present invention provides compounds ofFormula (V), or a pharmaceutically acceptable salt thereof, wherein X isCH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₉ are H; and R₈ isaryl wherein the aryl is phenyl.

In another embodiment, the present invention provides compounds ofFormula (V), or a pharmaceutically acceptable salt thereof, wherein X isCH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ is Cl,F, or CN; R₄ is H; R₅ is H; R₆ and R₉ are H; and R₈ is aryl wherein thearyl is phenyl.

In another embodiment, the present invention provides compounds ofFormula (V), or a pharmaceutically acceptable salt thereof, wherein X isN; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃ is(C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆ and R₉ are H; andR₈ is aryl wherein the aryl is phenyl.

In another embodiment, the present invention provides compounds ofFormula (V), or a pharmaceutically acceptable salt thereof, wherein X isN; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆ and R₉ are H; and R₈ isaryl wherein the aryl is phenyl.

In another embodiment, the present invention provides compounds ofFormula (V), or a pharmaceutically acceptable salt thereof, wherein X isN; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ is Cl,F, or CN; R₄ is H; R₅ is H; R₆ and R₉ are H; and R₈ is aryl wherein thearyl is phenyl.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (V), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient, diluent, or carrier.

In another embodiment, the present invention provides a method fortreating or preventing metabolic disorders in a mammal, particularly ahuman, where the metabolic disorder is ameliorated by activation of 5′adenosine monophosphate-activated protein kinase comprisingadministering to the mammal or human, in need of such treatment, atherapeutically effective amount of a compound of Formula (V), or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing type II diabetes in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(V), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing obesity in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(V), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing dyslipidemia in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(V), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing renal diseases in a mammal, particularly a human,where the renal disease is ameliorated by activation of 5′ adenosinemonophosphate-activated protein kinase comprising administering to themammal or human, in need of such treatment, a therapeutically effectiveamount of a compound of Formula (V), or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method fortreating or preventing chronic kidney disease in a mammal, particularlya human, comprising administering to the mammal or human, in need ofsuch treatment, a therapeutically effective amount of a compound ofFormula (V), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(V), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing acute kidney injury in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(V), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing polycystic kidney disease in a mammal,particularly a human, comprising administering to the mammal or human,in need of such treatment, a therapeutically effective amount of acompound of Formula (V), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides uses for compounds ofFormula (V), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treatingmetabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (V), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing type II diabetes in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (V), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (V), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (V) for preparing, or for the manufacture of, a medicament fortreating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (V) for preparing, or for the manufacture of, a medicament fortreating or preventing chronic kidney disease in a mammal, particularlya human.

In another aspect, the present invention provides uses for compounds ofFormula (V) for preparing, or for the manufacture of, a medicament fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (V) for preparing, or for the manufacture of, a medicament fortreating or preventing acute kidney injury in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (V) for preparing, or for the manufacture of, a medicament fortreating or preventing polycystic kidney disease in a mammal,particularly a human.

In another embodiment, the present invention provides compounds ofFormula (VI)

or a pharmaceutically acceptable salt thereof, wherein X is N or CH; Lis a bond, O, S, NR_(A), (C₁-C₆)alkylene, (C₂-C₆)alkenylene, or(C₂-C₆)alkynylene; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C), —S(O₂)OR_(A),—S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; and R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (VI), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, and R₁₀are H; and R₉ is H or hydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (VI), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, and R₁₀ are H; and R₉is H or hydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (VI), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and R₁₀ are H; and R₉ ishydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (VI), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H.

In another embodiment, the present invention provides compounds ofFormula (VI), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; R₆, R₇, and R₁₀are H; and R₉ is H or hydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (VI), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; R₆, R₇, and R₁₀ are H; and R₉is H or hydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (VI), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, and R₁₀ are H; and R₉ ishydroxy(C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (VI), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; R₆, R₇, R₉, and R₁₀ are H.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (VI), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient, diluent, or carrier.

In another embodiment, the present invention provides a method fortreating or preventing metabolic disorders in a mammal, particularly ahuman, where the metabolic disorder is ameliorated by activation of 5′adenosine monophosphate-activated protein kinase comprisingadministering to the mammal or human, in need of such treatment, atherapeutically effective amount of a compound of Formula (VI), or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing type II diabetes in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VI), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing obesity in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VI), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing dyslipidemia in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VI), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing renal diseases in a mammal, particularly a human,where the renal disease is ameliorated by activation of 5′ adenosinemonophosphate-activated protein kinase comprising administering to themammal or human, in need of such treatment, a therapeutically effectiveamount of a compound of Formula (VI), or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method fortreating or preventing chronic kidney disease in a mammal, particularlya human, comprising administering to the mammal or human, in need ofsuch treatment, a therapeutically effective amount of a compound ofFormula (VI), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VI), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing acute kidney injury in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VI), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing polycystic kidney disease in a mammal,particularly a human, comprising administering to the mammal or human,in need of such treatment, a therapeutically effective amount of acompound of Formula (VI), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides uses for compounds ofFormula (V), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treatingmetabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VI), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing type II diabetes in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VI), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VI), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VI) for preparing, or for the manufacture of, a medicament fortreating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VI) for preparing, or for the manufacture of, a medicament fortreating or preventing chronic kidney disease in a mammal, particularlya human.

In another aspect, the present invention provides uses for compounds ofFormula (VI) for preparing, or for the manufacture of, a medicament fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (VI) for preparing, or for the manufacture of, a medicament fortreating or preventing acute kidney injury in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (VI) for preparing, or for the manufacture of, a medicament fortreating or preventing polycystic kidney disease in a mammal,particularly a human.

In another embodiment, the present invention provides compounds ofFormula (VII)

or a pharmaceutically acceptable salt thereof, wherein X is N or CH; Lis a bond, O, S, NR_(A), (C₁-C₆)alkylene, (C₂-C₆)alkenylene, or(C₂-C₆)alkynylene; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C), —S(O₂)OR_(A),—S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; and R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (VII), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; and R₆, R₇, R₉,and R₁₀ are H.

In another embodiment, the present invention provides compounds ofFormula (VII), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀ areH.

In another embodiment, the present invention provides compounds ofFormula (VII), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀ are H.

In another embodiment, the present invention provides compounds ofFormula (VII), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; and R₆, R₇, R₉,and R₁₀ are H.

In another embodiment, the present invention provides compounds ofFormula (VII), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀ areH.

In another embodiment, the present invention provides compounds ofFormula (VII), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀ are H.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (VII), or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the present invention provides a method fortreating or preventing metabolic disorders in a mammal, particularly ahuman, where the metabolic disorder is ameliorated by activation of 5′adenosine monophosphate-activated protein kinase comprisingadministering to the mammal or human, in need of such treatment, atherapeutically effective amount of a compound of Formula (VII), or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing type II diabetes in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing obesity in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing dyslipidemia in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing renal diseases in a mammal, particularly a human,where the renal disease is ameliorated by activation of 5′ adenosinemonophosphate-activated protein kinase comprising administering to themammal or human, in need of such treatment, a therapeutically effectiveamount of a compound of Formula (VII), or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method fortreating or preventing chronic kidney disease in a mammal, particularlya human, comprising administering to the mammal or human, in need ofsuch treatment, a therapeutically effective amount of a compound ofFormula (VII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing acute kidney injury in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing polycystic kidney disease in a mammal,particularly a human, comprising administering to the mammal or human,in need of such treatment, a therapeutically effective amount of acompound of Formula (VII), or a pharmaceutically acceptable saltthereof.

In another aspect, the present invention provides uses for compounds ofFormula (VII), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treatingmetabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VII), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing type II diabetes in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VII), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VII), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VII) for preparing, or for the manufacture of, a medicament fortreating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VII) for preparing, or for the manufacture of, a medicament fortreating or preventing chronic kidney disease in a mammal, particularlya human.

In another aspect, the present invention provides uses for compounds ofFormula (VII) for preparing, or for the manufacture of, a medicament fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (VII) for preparing, or for the manufacture of, a medicament fortreating or preventing acute kidney injury in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (VII) for preparing, or for the manufacture of, a medicament fortreating or preventing polycystic kidney disease in a mammal,particularly a human.

In another embodiment, the present invention provides compounds ofFormula (VIII)

or a pharmaceutically acceptable salt thereof, wherein X is N or CH; Lis a bond, O, S, NR_(A), (C₁-C₆)alkylene, (C₂-C₆)alkenylene, or(C₂-C₆)alkynylene; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C), —S(O₂)OR_(A),—S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; and R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (VIII), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; and R₆, R₇, R₉,and R₁₀ are H.

In another embodiment, the present invention provides compounds ofFormula (VIII), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀ areH.

In another embodiment, the present invention provides compounds ofFormula (VIII), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀ are H.

In another embodiment, the present invention provides compounds ofFormula (VIII), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; and R₆, R₇, R₉,and R₁₀ are H.

In another embodiment, the present invention provides compounds ofFormula (VIII), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀ areH.

In another embodiment, the present invention provides compounds ofFormula (VIII), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀ are H.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (VIII), or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient, diluent, or carrier.

In another embodiment, the present invention provides a method fortreating or preventing metabolic disorders in a mammal, particularly ahuman, where the metabolic disorder is ameliorated by activation of 5′adenosine monophosphate-activated protein kinase comprisingadministering to the mammal or human, in need of such treatment, atherapeutically effective amount of a compound of Formula (VIII), or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing type II diabetes in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VIII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing obesity in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VIII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing dyslipidemia in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VIII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing renal diseases in a mammal, particularly a human,where the renal disease is ameliorated by activation of 5′ adenosinemonophosphate-activated protein kinase comprising administering to themammal or human, in need of such treatment, a therapeutically effectiveamount of a compound of Formula (VIII), or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method fortreating or preventing chronic kidney disease in a mammal, particularlya human, comprising administering to the mammal or human, in need ofsuch treatment, a therapeutically effective amount of a compound ofFormula (VIII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VIII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing acute kidney injury in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(VIII), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing polycystic kidney disease in a mammal,particularly a human, comprising administering to the mammal or human,in need of such treatment, a therapeutically effective amount of acompound of Formula (VIII), or a pharmaceutically acceptable saltthereof.

In another aspect, the present invention provides uses for compounds ofFormula (VIII), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treatingmetabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VIII), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing type II diabetes in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VIII), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VIII), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VIII) for preparing, or for the manufacture of, a medicamentfor treating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VIII) for preparing, or for the manufacture of, a medicamentfor treating or preventing chronic kidney disease in a mammal,particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VIII) for preparing, or for the manufacture of, a medicamentfor treating or preventing diabetic nephropathy in a mammal,particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (VIII) for preparing, or for the manufacture of, a medicamentfor treating or preventing acute kidney injury in a mammal, particularlya human.

In another aspect, the present invention provides uses for compounds ofFormula (VIII) for preparing, or for the manufacture of, a medicamentfor treating or preventing polycystic kidney disease in a mammal,particularly a human.

In another embodiment, the present invention provides compounds ofFormula (IX)

or a pharmaceutically acceptable salt thereof, wherein X is N or CH; Lis a bond, O, S, NR_(A), (C₁-C₆)alkylene, (C₂-C₆)alkenylene, or(C₂-C₆)alkynylene; R₁ is —C(O)OR_(A), —C(O)NR_(B)R_(C), —S(O₂)OR_(A),—S(O₂)NHC(O)R_(D), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, or1H-tetrazol-5-yl; R_(A) is H or (C₁-C₆)alkyl; R_(B) and R_(C) areindependently H, (C₁-C₆)alkyl, or —S(O₂)R_(D); R_(D) is (C₁-C₆)alkyl,—CF₃, or phenyl, wherein the phenyl is optionally substituted with 1, 2,3, 4, or 5 substituents that are independently (C₁-C₆)alkoxy,(C₁-C₆)alkyl, cyano, halogen, halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy, mercapto, nitro, or NR_(E)R_(F); R_(E) and R_(F) areindependently H or (C₁-C₆)alkyl; R₂, R₃, and R₄ are independently H,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₁-C₆)alkylthio, carboxy, cyano, halogen,halo(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₈)alkyl,mercapto, nitro, —NR_(G)R_(H), or (NR_(G)R_(H))carbonyl; R_(G) and R_(H)are independently H, (C₁-C₆)alkyl, or (C₁-C₆)alkylcarbonyl; R₅ is H or(C₁-C₆)alkyl; R₆, R₇, R₉, and R₁₀ are independently H, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, (C₁-C₆)alkylcarbonyl,(C₁-C₆)alkylthio, carboxy, cyano, halogen, halo(C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, hydroxy, hydroxy(C₁-C₆)alkyl, mercapto, nitro,—NR_(J)R_(K), or (NR_(J)R_(K))carbonyl; and R_(J) and R_(K) areindependently H or (C₁-C₆)alkyl.

In another embodiment, the present invention provides compounds ofFormula (IX), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen;R₃ is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; and R₆, R₇, R₉,and R₁₀ are H.

In another embodiment, the present invention provides compounds ofFormula (IX), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀ areH.

In another embodiment, the present invention provides compounds ofFormula (IX), or a pharmaceutically acceptable salt thereof, wherein Xis CH; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ isCl, F, or CN; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀ are H.

In another embodiment, the present invention provides compounds ofFormula (IX), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or halogen; R₃is (C₁-C₆)alkyl, cyano, or halogen; R₄ is H; R₅ is H; and R₆, R₇, R₉,and R₁₀ are H.

In another embodiment, the present invention provides compounds ofFormula (IX), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —C(O)OR_(A); R_(A) is H; R₂ is H or F; R₃ ismethyl, cyano, Cl, or F; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀ areH.

In another embodiment, the present invention provides compounds ofFormula (IX), or a pharmaceutically acceptable salt thereof, wherein Xis N; L is a bond; R₁ is —(CH₂)_(n)C(O)OR_(A); R_(A) is H; n is 0; R₂ isH or F; R₃ is Cl, F, or CN; R₄ is H; R₅ is H; and R₆, R₇, R₉, and R₁₀are H.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (IX), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient, diluent, or carrier.

In another embodiment, the present invention provides a method fortreating or preventing metabolic disorders in a mammal, particularly ahuman, where the metabolic disorder is ameliorated by activation of 5′adenosine monophosphate-activated protein kinase comprisingadministering to the mammal or human, in need of such treatment, atherapeutically effective amount of a compound of Formula (IX), or apharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing type II diabetes in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(IX), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing obesity in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(IX), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing dyslipidemia in a mammal, particularly a human,comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(IX), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing renal diseases in a mammal, particularly a human,where the renal disease is ameliorated by activation of 5′ adenosinemonophosphate-activated protein kinase comprising administering to themammal or human, in need of such treatment, a therapeutically effectiveamount of a compound of Formula (IX), or a pharmaceutically acceptablesalt thereof.

In another embodiment, the present invention provides a method fortreating or preventing chronic kidney disease in a mammal, particularlya human, comprising administering to the mammal or human, in need ofsuch treatment, a therapeutically effective amount of a compound ofFormula (IX), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(IX), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing acute kidney injury in a mammal, particularly ahuman, comprising administering to the mammal or human, in need of suchtreatment, a therapeutically effective amount of a compound of Formula(IX), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method fortreating or preventing polycystic kidney disease in a mammal,particularly a human, comprising administering to the mammal or human,in need of such treatment, a therapeutically effective amount of acompound of Formula (IX), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides uses for compounds ofFormula (IX), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treatingmetabolic disorders in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (IX), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing type II diabetes in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (IX), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing obesity in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (IX), or a pharmaceutically acceptable salt thereof, forpreparing, or for the manufacture of, a medicament for treating orpreventing dyslipidemia in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (IX) for preparing, or for the manufacture of, a medicament fortreating renal diseases in a mammal, particularly a human.

In another aspect, the present invention provides uses for compounds ofFormula (IX) for preparing, or for the manufacture of, a medicament fortreating or preventing chronic kidney disease in a mammal, particularlya human.

In another aspect, the present invention provides uses for compounds ofFormula (IX) for preparing, or for the manufacture of, a medicament fortreating or preventing diabetic nephropathy in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (IX) for preparing, or for the manufacture of, a medicament fortreating or preventing acute kidney injury in a mammal, particularly ahuman.

In another aspect, the present invention provides uses for compounds ofFormula (IX) for preparing, or for the manufacture of, a medicament fortreating or preventing polycystic kidney disease in a mammal,particularly a human.

DEFINITIONS

As used throughout this specification and the appended claims, thefollowing terms have the following meanings.

The term “(C₂-C₈)alkenylene” means a divalent group derived from astraight or branched chain hydrocarbon of from 2 to 8 carbon atomscontaining at least one double bond. Representative examples ofalkenylene include, but are not limited to, —CH═CH—, —CH═CH₂CH₂—, and—CH═C(CH₃)CH₂—.

The term “(C₁-C₆)alkoxy” as used herein, means a (C₁-C₆)alkyl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom.

Representative examples of (C₁-C₆)alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy,and hexyloxy.

The term “(C₁-C₆)alkoxy(C₁-C₆)alkoxy” as used herein, means a(C₁-C₆)alkoxy group, as defined herein, appended to the parent molecularmoiety through another (C₁-C₆)alkoxy group, as defined herein.Representative examples of (C₁-C₆)alkoxy(C₁-C₆)alkoxy include, but arenot limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, andmethoxymethoxy.

The term “(C₁-C₆)alkoxy(C₁-C₆)alkyl” as used herein, means a(C₁-C₆)alkoxy group, as defined herein, appended to the parent molecularmoiety through a (C₁-C₆)alkyl group, as defined herein. Representativeexamples of (C₁-C₆)alkoxy(C₁-C₆)alkyl include, but are not limited to,tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

The term “(C₁-C₆)alkoxycarbonyl” as used herein, means a (C₁-C₆)alkoxygroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(C₁-C₆)alkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “(C₁-C₆)alkoxysulfonyl” as used herein, means a (C₁-C₆)alkoxygroup, as defined herein, appended appended to the parent molecularmoiety through a sulfonyl group, as defined herein. Representativeexamples of (C₁-C₆)alkoxysulfonyl include, but are not limited to,methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.

The term “(C₁-C₆)alkyl” as used herein, means a straight or branchedchain hydrocarbon containing from 1 to 6 carbon atoms. Representativeexamples of (C₁-C₆)alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term “(C₁-C₆)alkylcarbonyl” as used herein, means a (C₁-C₆)alkylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(C₁-C₆)alkylcarbonyl include, but are not limited to, acetyl,1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “(C₁-C₆)alkylene” means a divalent group derived from astraight or branched chain hydrocarbon of from 1 to 6 carbon atoms.Representative examples of (C₁-C₈)alkylene include, but are not limitedto, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,—CH₂CH(CH₃)CH₂—, and —CH₂CH₂CH₂CH₂CH₂CH₂—.

The term “(C₁-C₆)alkylsulfonyl” as used herein, means an (C₁-C₆)alkylgroup, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(C₁-C₆)alkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “(C₁-C₆)alkylthio” as used herein, means a (C₁-C₆)alkyl group,as defined herein, appended to the parent molecular moiety through asulfur atom. Representative examples of (C₁-C₆)alkylthio include, butare not limited to, methylthio, ethylthio, tert-butylthio, andhexylthio.

The term “aryl” as used herein, means a phenyl or naphthyl group.

The term “aryl(C₁-C₆)alkoxy” as used herein, means an aryl group, asdefined herein, appended to the parent molecular moiety through an(C₁-C₆)alkoxy group, as defined herein.

The term “aryl(C₁-C₆)alkyl” as used herein, means an aryl group, asdefined herein, appended to the parent molecular moiety through an(C₁-C₆)alkyl group, as defined herein. Representative examples ofaryl(C₁-C₆)alkyl include, but are not limited to, benzyl, 2-phenylethyl,3-phenylpropyl, and 2-naphth-2-ylethyl.

The term “arylcarbonyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Examples of arylcarbonyl are benzoyl andnaphthoyl.

The term “aryloxy” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Examples of aryloxy are phenoxy and naphthalenyloxy.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —C(O)OH group.

The term “carboxy(C₁-C₆)alkoxy” as used herein, means a carboxy group,as defined herein, is attached to the parent molecular moiety through a(C₁-C₆)alkoxy group, as defined herein.

The term “carboxy(C₁-C₆)alkyl” as used herein, means a carboxy group, asdefined herein, is attached to the parent molecular moiety through a(C₁-C₆)alkyl group, as defined herein.

The term “cyano” as used herein, means a —CN group.

The term “(C₃-C₈)cycloalkyl” as used herein, means a saturated cyclichydrocarbon group containing from 3 to 8 carbons, examples of(C₃-C₈)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl.

The term “(C₃-C₈)cycloalkyl(C₁-C₆)alkoxy” as used herein, means a(C₃-C₈)cycloalkyl group, as defined herein, appended to the parentmolecular moiety through a (C₁-C₆)alkoxy group, as defined herein.

The term “(C₃-C₈)cycloalkyl(C₁-C₆)alkyl” as used herein, means a(C₃-C₆)cycloalkyl group, as defined herein, appended to the parentmolecular moiety through a (C₁-C₆)alkyl group, as defined herein.Representative examples of (C₃-C₈)cycloalkyl(C₁-C₆)alkyl include, butare not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term “(C₃-C₈)cycloalkylcarbonyl” as used herein, means(C₃-C₈)cycloalkyl group, as defined herein, appended to the parentmolecular moiety through a carbonyl group, as defined herein.Representative examples of (C₃-C₈)cycloalkylcarbonyl include, but arenot limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl, andcyclohexylcarbonyl.

The term “(C₃-C₈)cycloalkyloxy” as used herein, means (C₃-C₈)cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom, as defined herein. Representative examples of(C₃-C₈)cycloalkyloxy include, but are not limited to, cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, andcyclooctyloxy.

The term “Formula (I-IX)” as used herein means compounds of Formula (I),(II), (III), (IV), (V), (VI), (VII), (VIII), and (IX).

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “halo(C₁-C₆)alkoxy” as used herein, means at least one halogen,as defined herein, appended to the parent molecular moiety through a(C₁-C₆)alkoxy group, as defined herein. Representative examples ofhalo(C₁-C₆)alkoxy include, but are not limited to, chloromethoxy,2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

The term “halo(C₁-C₆)alkyl” as used herein, means at least one halogen,as defined herein, appended to the parent molecular moiety through a(C₁-C₆)alkyl group, as defined herein. Representative examples ofhalo(C₁-C₆)alkyl include, but are not limited to, chloromethyl,2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and2-chloro-3-fluoropentyl.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora bicyclic heteroaryl. The monocyclic heteroaryl is a 5 or 6 memberedring. The 5 membered ring consists of two double bonds and one, two,three or four nitrogen atoms and/or optionally one oxygen or sulfuratom. The 6 membered ring consists of three double bonds and one, two,three or four nitrogen atoms. The 5 or 6 membered heteroaryl isconnected to the parent molecular moiety through any carbon atom or anynitrogen atom contained within the heteroaryl. Representative examplesof monocyclic heteroaryl include, but are not limited to, furyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclicheteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or amonocyclic heteroaryl fused to a cycloalkyl, or a monocyclic heteroarylfused to a cycloalkenyl, or a monocyclic heteroaryl fused to amonocyclic heteroaryl. The bicyclic heteroaryl is connected to theparent molecular moiety through any carbon atom or any nitrogen atomcontained within the bicyclic heteroaryl. Representative examples ofbicyclic heteroaryl include, but are not limited to, benzimidazolyl,benzofuranyl, benzothienyl, benzoxadiazolyl, cinnolinyl,dihydroquinolinyl, dihydroisoquinolinyl, furopyridinyl, indazolyl,indolyl, isoquinolinyl, naphthyridinyl, quinolinyl,tetrahydroquinolinyl, and thienopyridinyl.

The term “heteroaryl(C₁-C₆)alkoxy” as used herein, means a heteroarylgroup, as defined herein, appended to the parent molecular moietythrough an (C₁-C₆)alkoxy group, as defined herein. Representativeexamples of heteroaryl(C₁-C₆)alkoxy include, but are not limited to,fur-3-ylmethoxy, 1H-imidazol-2-ylmethoxy, 1H-imidazol-4-ylmethoxy,1-(pyridin-4-yl)ethoxy, pyridin-3-ylmethoxy,6-chloropyridin-3-ylmethoxy, pyridin-4-ylmethoxy,(6-(trifluoromethyl)pyridin-3-yl)methoxy,(6-(cyano)pyridin-3-yl)methoxy, (2-(cyano)pyridin-4-yl)methoxy,(5-(cyano)pyridin-2-yl)methoxy, (2-(chloro)pyridin-4-yl)methoxy,pyrimidin-5-ylmethoxy, 2-(pyrimidin-2-yl)propoxy, thien-2-ylmethoxy, andthien-3-ylmethoxy.

The term “heteroaryl(C₁-C₆)alkyl” as used herein, means a heteroaryl, asdefined herein, appended to the parent molecular moiety through an(C₁-C₆)alkyl group, as defined herein. Representative examples ofheteroaryl(C₁-C₆)alkyl include, but are not limited to, fur-3-ylmethyl,1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl,pyridin-3-ylmethyl, 6-chloropyridin-3-ylmethyl, pyridin-4-ylmethyl,(6-(trifluoromethyl)pyridin-3-yl)methyl, (6-(cyano)pyridin-3-yl)methyl,(2-(cyano)pyridin-4-yl)methyl, (5-(cyano)pyridin-2-yl)methyl,(2-(chloro)pyridin-4-yl)methyl, pyrimidin-5-ylmethyl,2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.

The term “heteroarylcarbonyl” as used herein, means a heteroaryl group,as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofheteroarylcarbonyl include, but are not limited to, fur-3-ylcarbonyl,1H-imidazol-2-ylcarbonyl, 1H-imidazol-4-ylcarbonyl,pyridin-3-ylcarbonyl, 6-chloropyridin-3-ylcarbonyl,pyridin-4-ylcarbonyl, (6-(trifluoromethyl)pyridin-3-yl)carbonyl,(6-(cyano)pyridin-3-yl)carbonyl, (2-(cyano)pyridin-4-yl)carbonyl,(5-(cyano)pyridin-2-yl)carbonyl, (2-(chloro)pyridin-4-yl)carbonyl,pyrimidin-5-ylcarbonyl, pyrimidin-2-ylcarbonyl, thien-2-ylcarbonyl, andthien-3-ylcarbonyl.

The term “heteroaryloxy” as used herein, means a heteroaryl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom. Representative examples of heteroaryloxy include, but arenot limited to, fur-3-yloxy, 1H-imidazol-2-yloxy, 1H-imidazol-4-yloxy,pyridin-3-yloxy, 6-chloropyridin-3-yloxy, pyridin-4-yloxy,(6-(trifluoromethyl)pyridin-3-yl)oxy, (6-(cyano)pyridin-3-yl)oxy,(2-(cyano)pyridin-4-yl)oxy, (5-(cyano)pyridin-2-yl)oxy,(2-(chloro)pyridin-4-yl)oxy, pyrimidin-5-yloxy, pyrimidin-2-yloxy,thien-2-yloxy, and thien-3-yloxy.

The term “(C₃-C₇)heterocycle” or “(C₃-C₇)heterocyclic” as used herein,means a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatomindependently selected from the group consisting of 0, N, and S. The 3or 4 membered ring contains 1 heteroatom selected from the groupconsisting of O, N and S. The 5 membered ring contains zero or onedouble bond and one, two or three heteroatoms selected from the groupconsisting of O, N and S. The 6 or 7 membered ring contains zero, one ortwo double bonds and one, two or three heteroatoms selected from thegroup consisting of O, N and S. The heterocycle is connected to theparent molecular moiety through any carbon atom or any nitrogen atomcontained within the heterocycle. Representative examples of heterocycleinclude, but are not limited to, azetidinyl, azepanyl, aziridinyl,diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, andtrithianyl.

The term “(C₃-C₇)heterocycle(C₁-C₆)alkoxy” as used herein, means a 3-7membered heterocycle group, as defined herein, appended to the parentmolecular moiety through an (C₁-C₆)alkoxy group, as defined herein.

The term “(C₃-C₇)heterocycle(C₁-C₆)alkyl” as used herein, means a 3-7membered heterocycle, as defined herein, appended to the parentmolecular moiety through an (C₁-C₆)alkyl group, as defined herein.

The term “(C₃-C₇)heterocyclecarbonyl” as used herein, means a 3-7membered heterocycle, as defined herein, appended to the parentmolecular moiety through a carbonyl group, as defined herein.

The term “(C₃-C₇)heterocycleoxy” as used herein, means a 3-7 memberedheterocycle, as defined herein, appended to the parent molecular moietythrough an oxygen atom.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxy(C₁-C₆)alkoxy” as used herein, means at least onehydroxy group, as defined herein, is appended to the parent molecularmoiety through a (C₁-C₆)alkoxy group, as defined herein. Representativeexamples of hydroxy(C₁-C₆)alkoxy include, but are not limited to,hydroxymethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypentoxy,and 2-ethyl-4-hydroxyheptoxy.

The term “hydroxy(C₁-C₆)alkyl” as used herein, means at least onehydroxy group, as defined herein, is appended to the parent molecularmoiety through a (C₁-C₆)alkyl group, as defined herein. Representativeexamples of hydroxy(C₁-C₆)alkyl include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “mercapto” as used herein, means a —SH group.

The term “nitro” as used herein, means a —NO₂ group.

The term “nitrogen protecting group” as used herein, means those groupsintended to protect an amino group against undesirable reactions duringsynthetic procedures. Representative examples of a nitrogen protectinggroup include, but are not limited to, acetyl, benzoyl, benzyl,benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, pivaloyl,tert-butoxycarbonyl (Boc), tert-butylacetyl, ethyloxycarbonyl,trifluoroacetyl, triphenylmethyl (trityl), tert-butyldimethylsilane, andtriisopropylsilane.

The term “NR_(E)R_(F)” as used herein, means two groups, R_(E) andR_(F), which are appended to the parent molecular moiety through anitrogen atom. R_(E) and R_(F) are each independently H or (C₁-C₆)alkyl.Representative examples of NR_(E)R_(F) include, but are not limited to,amino, methylamino, dimethylamino, and ethylmethylamino.

The term “(NR_(E)R_(F))carbonyl” as used herein, means a NR_(E)R_(F)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(E)R_(F))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “NR_(G)R_(H)” as used herein, means two groups, R_(G) andR_(H), which are appended to the parent molecular moiety through anitrogen atom. R_(G) and R_(H) are each independently H, (C₁-C₆)alkyl,or (C₁-C₆)alkylcarbonyl. Representative examples of NR_(G)R_(H) include,but are not limited to, amino, methylamino, dimethylamino,ethylmethylamino, acetamido, propionamido, and isobutyramido.

The term “(NR_(G)R_(H))carbonyl” as used herein, means a NR_(G)R_(H)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(G)R_(H))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “NR_(J)R_(K)” as used herein, means two groups, R_(J) andR_(K), which are appended to the parent molecular moiety through anitrogen atom. R_(J) and R_(K) are each independently H or (C₁-C₆)alkyl.Representative examples of NR_(J)R_(K) include, but are not limited to,amino, methylamino, dimethylamino, and ethylmethylamino.

The term “(NR_(J)R_(K))carbonyl” as used herein, means a NR_(J)R_(K)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(J)R_(K))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “NR_(M)R_(N)” as used herein, means two groups, R_(M) andR_(N), which are appended to the parent molecular moiety through anitrogen atom. R_(M) and R_(N) are each independently H, (C₁-C₆)alkyl,or (C₁-C₆)alkylcarbonyl; or R_(M) and R_(N) together with the nitrogenthey are attached to form a 3 to 8 membered ring. Representativeexamples of NR_(M)R_(N) include, but are not limited to, amino,methylamino, dimethylamino, ethylmethylamino, aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, azepanyl, and azocanyl.

The term “NR_(M)R_(N)(C₁-C₆)alkoxy” as used herein, means a NR_(M)R_(N)group, as defined herein, appended to the parent molecular moietythrough a (C₁-C₆)alkoxy group, as defined herein.

The term “NR_(M)R_(N)(C₁-C₆)alkyl” as used herein, means a NR_(M)R_(N)group, as defined herein, appended to the parent molecular moietythrough a (C₁-C₆)alkyl group, as defined herein.

The term “(NR_(M)R_(N))carbonyl” as used herein, means a NR_(M)R_(N)group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(NR_(M)R_(N))carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “(NR_(M)R_(N))carbonyl(C₁-C₆)alkoxy” as used herein, means a(NR_(M)R_(N))carbonyl group, as defined herein, appended to the parentmolecular moiety through a (C₁-C₆)alkoxy group, as defined herein.

The term “(NR_(M)R_(N))carbonyl(C₁-C₆)alkyl” as used herein, means a(NR_(M)R_(N))carbonyl group, as defined herein, appended to the parentmolecular moiety through a (C₁-C₆)alkyl group, as defined herein.

The term “tautomer,” as used herein, means a proton shift from one atomof a molecule to another atom of the same molecule wherein two or morestructurally distinct compounds are in equilibrium with each other.Compounds of the present invention may exist as tautomers. The presentinvention contemplates tautomers due to proton shifts from one atom toanother atom of the same molecule generating two or more distinctcompounds that are in equilibrium with each other.

The term “therapeutically effective amount” means an amount of acompound of the present invention, or a pharmaceutically acceptable saltthereof, that: (i) treats the particular disease, condition, ordisorder, (ii) attenuates, ameliorates, or eliminates one or moresymptoms of the particular disease, condition, or disorder, or (iii)prevents or delays the onset of one or more symptoms of the particulardisease, condition, or disorder described herein.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. By “pharmaceutically acceptable salt” is meant those salts whichare, within the scope of sound medical judgement, suitable for use incontact with the tissues of humans and animals without undue toxicity,irritation, allergic response and the like and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell-known in the art. For example, S. M. Berge et al. describepharmaceutically acceptable salts in detail in J. PharmaceuticalSciences, 1977, 66:1-19. The salts can be prepared in situ during thefinal isolation and purification of the compounds of the presentinvention or separately by reacting a free base (basic nitrogen) with asuitable organic or inorganic acid. Representative acid addition saltsinclude, but are not limited to acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate,hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate. Also, the basicnitrogen-containing groups can be quaternized with such agents as loweralkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid and citric acid.

Compounds of the present invention may exist as stereoisomers whereinasymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Aool. Chem., (1976), 45: 13-30. The presentinvention contemplates various stereoisomers and mixtures thereof andare specifically included within the scope of this invention.Stereoisomers include enantiomers and diastereomers, and mixtures ofenantiomers or diastereomers. Individual stereoisomers of compounds ofthe present invention may be prepared synthetically from commerciallyavailable starting materials which contain asymmetric or chiral centersor by preparation of racemic mixtures followed by resolution well-knownto those of ordinary skill in the art. These methods of resolutioninclude, but are not limited to (1) attachment of a chiral auxiliary toa mixture of enantiomers, separation of the resulting mixture ofdiastereomers by recrystallization or chromatography, and liberation ofthe optically pure product from the auxiliary or (2) direct separationof the mixture of optical enantiomers on chiral chromatographic columns.

Compounds of the present invention may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The compounds of the present invention further include eachconformational isomer of compounds of Formula (I) and mixtures thereof.

Tautomers may exist in the compounds of the present invention and arespecifically included within the scope of the present invention. Thepresent invention contemplates tautomers due to proton shifts from oneatom to another atom of the same molecule generating two or morecompounds that are in equilibrium with each other. The compounds of thepresent invention may be isolated and used per se or in the form oftheir pharmaceutically acceptable salts. In accordance with the presentinvention, compounds with multiple basic nitrogen atoms can form saltswith varying number of equivalents (“eq.”) of acid. It will beunderstood by practitioners that all such salts are within the scope ofthe present invention.

Compounds of the present invention may exist in more than one crystalform. Polymorphs of compounds of Formula I-IX and salts thereof(including solvates and hydrates) form part of this invention and may beprepared by crystallization of a compound of the present invention underdifferent conditions. For example, using different solvents or differentsolvent mixtures for recrystallization; crystallization at differenttemperatures; various modes of cooling, ranging from very fast to veryslow cooling during crystallization. Polymorphs may also be obtained byheating or melting a compound of the present invention followed bygradual or fast cooling. The presence of polymorphs may be determined bysolid probe nuclear magnetic resonance (NMR) spectroscopy, infrared (IR)spectroscopy, differential scanning calorimetry, powder X-raydiffraction or such other techniques.

This invention also includes isotopically-labeled compounds, which areidentical to those described by Formula I-IX, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,sulfur and fluorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ³⁶Cl,¹²⁵I, ¹²⁹I, and ¹⁸F respectively. Certain isotopically-labeled compoundsof the present invention, for example those into which radioactiveisotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated (i.e., ³H), andcarbon-14 (i.e., ¹⁴C), isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withheavier isotopes such as deuterium (i.e., ²H), can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically labeledcompounds of the present invention can generally be prepared by carryingout the procedures disclosed in the schemes and/or in the Examplesbelow, by substituting a readily available isotopically labeled reagentfor a non-isotopically labeled reagent.

Compounds of the present invention are useful for treating diseases,conditions and/or disorders ameliorated via activation of AMPK. Anotherembodiment of the present invention is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thepresent invention and a pharmaceutically acceptable excipient, diluentor carrier. The compounds of the present invention (including thecompositions and processes used herein) may also be used in themanufacture of a medicament for the therapeutic applications describedherein.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water, and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected based on solvents recognized by persons skilled inthe art as safe (GRAS) to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., for use in the preparing a medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent)) is dissolved in a suitable solvent in the presence of one ormore of the excipients described above. The dissolution rate of poorlywater-soluble compounds may be enhanced by the use of a spray-drieddispersion, such as those described by Takeuchi, H., et al. in“Enhancement of the dissolution rate of a poorly water-soluble drug(tolbutamide) by a spray-drying solvent deposition method anddisintegrants” J. Pharm. Pharmacol., 39, 769-773 (1987); and EP0901786B1 (US2002/009494), incorporated herein by reference. The compound ofthe present invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable dosage of the drug and to givethe patient an elegant and easily handleable product.

The pharmaceutical compositions also include solvates and hydrates ofthe compounds of the present invention. The term “solvate” refers to amolecular complex of a compound represented by Formula (I)-(IX),including pharmaceutically acceptable salts thereof, with one or moresolvent molecules. Such solvent molecules are those commonly used in thepharmaceutical art, which are known to be innocuous to the recipient,e.g., water, ethanol, ethylene glycol, and the like, The term “hydrate”refers to the complex where the solvent molecule is water. The solvatesand/or hydrates preferably exist in crystalline form. Other solvents maybe used as intermediate solvates in the preparation of more desirablesolvates, such as methanol, methyl t-butyl ether, ethyl acetate, methylacetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butyne-diol,and the like.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The present invention provides a method of treating diseases, conditionsand/or disorders activated by the activation of AMPK in an animal,particularly a human, that includes administering to the animal or humanin need of such treatment a therapeutically effective amount of acompound of the present invention or a pharmaceutical compositioncomprising an effective amount of a compound of the present inventionand a pharmaceutically acceptable excipient, diluent, or carrier. Themethod is particularly useful for treating diseases, conditions and/ordisorders that benefit from the activation of AMPK.

One aspect of the present invention is the treatment of obesity, andobesity-related disorders (e.g., overweight, weight gain, or weightmaintenance). Obesity and overweight are generally defined by body massindex (BMI), which is correlated with total body fat and estimates therelative risk of disease. BMI is calculated by weight in kilogramsdivided by height in meters squared (kg/m²). Overweight is typicallydefined as a BMI of 25-29.9 kg/m², and obesity is typically defined as aBMI of 30 kg/m². See, e.g., National Heart, Lung, and Blood Institute,Clinical Guidelines on the Identification, Evaluation, and Treatment ofOverweight and Obesity in Adults, The Evidence Report, Washington, D.C.:U.S. Department of Health and Human Services, NIH publication no.98-4083 (1998).

Another aspect of the present invention is for the treatment (e.g.,delaying the progression or onset) of diabetes or diabetes-relateddisorders including Type 1 and Type 2 diabetes, impaired glucosetolerance, insulin resistance, hyperglycemia, and diabetic complicationssuch as atherosclerosis, coronary heart disease, stroke, peripheralvascular disease, nephropathy, hypertension, neuropathy, andretinopathy.

In yet another aspect of the present invention is the treatment ofobesity co-morbidities, such as metabolic syndrome. Metabolic syndromeincludes diseases, conditions or disorders such as dyslipidemia,hypertension, insulin resistance, diabetes (e.g., Type 2 diabetes),coronary artery disease and heart failure. For more detailed informationon Metabolic Syndrome, see, e.g., Zimmet, P. Z., et al., “The MetabolicSyndrome: Perhaps an Etiologic Mystery but Far From a Myth—Where Doesthe International Diabetes Federation Stand?,” Diabetes & Endocrinology,7(2), (2005); and Alberti, K. G., et al., “The Metabolic Syndrome—A NewWorldwide Definition,” Lancet, 366, 1059-62 (2005). Preferably,administration of the compounds of the present invention provides astatistically significant (p<0.05) reduction in at least onecardiovascular disease risk factor, such as lowering of plasma leptin,C-reactive protein (CRP) and/or cholesterol, as compared to a vehiclecontrol containing no drug. The administration of compounds of thepresent invention may also provide a statistically significant (p<0.05)reduction in glucose serum levels.

In yet another aspect of the invention is the treatment of nonalcoholicfatty liver disease (NAFLD) and hepatic insulin resistance.

The present invention also provides pharmaceutical compositions whichcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions may be specially formulated for oraladministration in solid or liquid form, for parenteral injection, or forrectal administration.

The compounds of the present invention or pharmaceutical compositionsthereof can be administered to humans and other mammals orally,rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments or drops),bucally or as an oral or nasal spray. The term “parenterally,” as usedherein, refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous,intraarticular injection and infusion.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms may be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Suspensions, in addition to the active compounds, may contain suspendingagents, as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, andmixtures thereof.

For a normal adult human having a body weight of about 100 kg, a dosagein the range of from about 0.001 mg to about 10 mg per kilogram bodyweight is typically sufficient, preferably from about 0.01 mg/kg toabout 5.0 mg/kg, more preferably from about 0.01 mg/kg to about 1 mg/kg.However, some variability in the general dosage range may be requireddepending upon the age and weight of the subject being treated, theintended route of administration, the particular compound beingadministered and the like. The determination of dosage ranges andoptimal dosages for a particular patient is well within the ability ofone of ordinary skill in the art having the benefit of the instantdisclosure. It is also noted that the compounds of the present inventioncan be used in sustained release, controlled release, and delayedrelease formulations, which forms are also well known to one of ordinaryskill in the art.

The compounds of this invention may also be used in conjunction withother pharmaceutical agents for the treatment of the diseases,conditions and/or disorders described herein. Therefore, methods oftreatment that include administering compounds of the present inventionin combination with other pharmaceutical agents are also provided.Suitable pharmaceutical agents that may be used in combination with thecompounds of the present invention include anti-obesity agents(including appetite suppressants), anti-diabetic agents,anti-hyperglycemic agents, lipid lowering agents, and anti-hypertensiveagents.

Suitable lipid lowering agents that can be combined with the compoundsof the present invention include, for example, those described at page30, line 20 through page 31, line 30 of WO 2011005611. The lipidlowering agents include bile acid sequestrants, HMG-CoA reductaseinhibitors, HMG-CoA synthase inhibitors, cholesterol absorptioninhibitors, acyl coenzyme A-cholesterol acyl transferase (ACAT)inhibitors, CETP inhibitors, squalene synthetase inhibitors, PPAR aagonists, FXR receptor modulators, LXR receptor modulators, lipoproteinsynthesis inhibitors, rennin angiotensisn system inhibitors, PPAR dpartial agonists, bile acid reabsorption inhibitors, PPAR γ agonists,triglyceride synthesis inhibitors, microsomal triglyceride transportinhibitors, transcription modulators, squalene epoxidase inhibitors, lowdensity lipoprotein receptor inducers, platelet aggregation inhibitors,5-LO or FLAP inhibitors, niacin bound chromium and other agents thataffect lipid composition.

Suitable anti-hypertensive agents that can be combined with thecompounds of the present invention include, for example, those describedat page 31, line 31 through page 32, line 18 of WO 2011005611. Theanti-hypertensive agents include diuretics, beta-adrenergic blockers,calcium channel blockers, angiotensin converting enzyme (ACE)inhibitors, neutral endopeptidase inhibitors, endothelin antagonists,vasodilators, angiotensin II receptor antagonists, a/6 adrenergicblockers, alpha 1 blockers, alpha 2 agonists, aldosterone inhibitors,mineraocorticoid receptor inhibitors, renin inhibitors andangiopoietin-2-binding agents.

Suitable anti-diabetic agents include an acetyl-CoA carboxylase-(ACC)inhibitor such as those described in WO2009144554, WO2003072197,WO2009144555 and WO2008065508, a diacylglycerol O-acyltransferase 1(DGAT-1) inhibitor, such as those described in WO09016462 orWO2010086820, AZD7687 or LCQ908, diacylglycerol O-acyltransferase 2(DGAT-2) inhibitor, monoacylglycerol O-acyltransferase inhibitors, aphosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea(e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide,glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone,glisolamide, tolazamide, and tolbutamide), a meglitinide, an α-amylaseinhibitor (e.g., tendamistat, trestatin and AL-3688), an α-glucosidehydrolase inhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g.,adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q,and salbostatin), a PPARγ agonist (e.g., balaglitazone, ciglitazone,darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone andtroglitazone), a PPAR α/γ agonist (e.g., CLX-0940, GW-1536, GW-1929,GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide(e.g., metformin), a glucagon-like peptide 1 (GLP-1) modulator such asan agonist (e.g., exendin-3 and exendin-4), liraglutide, albiglutide,exenatide (Byetta®), albiglutide, taspoglutide, lixisenatide,dulaglutide, semaglutide, NN-9924, TTP-054, a protein tyrosinephosphatase-1B (PTP-1B) inhibitor (e.g., trodusquemine, hyrtiosalextract, and compounds disclosed by Zhang, S., et al., Drug DiscoveryToday, 12(9/10), 373-381 (2007)), SIRT-1 inhibitor (e.g., resveratrol,GSK2245840 or GSK184072), a dipeptidyl peptidease IV (DPP-IV) inhibitor(e.g., those in WO2005116014, sitagliptin, vildagliptin, alogliptin,dutogliptin, linagliptin and saxagliptin), an insulin secreatagogue, afatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminalkinase (JNK) inhibitor, glucokinase activators (GKa) such as thosedescribed in WO2010103437, WO2010103438, WO2010013161, WO2007122482,TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658or GKM-001, insulin, an insulin mimetic, a glycogen phosphorylaseinhibitor (e.g. GSK1362885), a VPAC2 receptor agonist, SGLT2 inhibitors,such as those described in E. C. Chao et al. Nature Reviews DrugDiscovery 9, 551-559 (July 2010) including dapagliflozin, canagliflozin,BI-10733, tofogliflozin (CSG452), ASP-1941, THR1474, TS-071, ISIS388626and LX4211 as well as those in WO2010023594, a glucagon receptormodulator such as those described in Demong, D. E. et al. Annual Reportsin Medicinal Chemistry 2008, 43, 119-137, GPR119 modulators,particularly agonists, such as those described in WO2010140092,WO2010128425, WO2010128414, WO2010106457, Jones, R. M. et al. inMedicinal Chemistry 2009, 44, 149-170 (e.g. MBX-2982, GSK1292263, APD597and PSN821), FGF21 derivatives or analogs such as those described inKharitonenkov, A. et al. et al., Current Opinion in InvestigationalDrugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators,particularly agonists, such as those described in Zhong, M., CurrentTopics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40agonists, such as those described in Medina, J.C., Annual Reports inMedicinal Chemistry, 2008, 43, 75-85, including but not limited toTAK-875, GPR120 modulators, particularly agonists, high affinitynicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, suchas GSK1614235. A further representative listing of anti-diabetic agentsthat can be combined with the compounds of the present invention can befound, for example, at page 28, line 35 through page 30, line 19 ofWO2011005611. Preferred anti-diabetic agents are metformin and DPP-IVinhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin,linagliptin and saxagliptin). Other antidiabetic agents could includeinhibitors or modulators of carnitine palmitoyl transferase enzymes,inhibitors of fructose 1,6-diphosphatase, inhibitors of aldosereductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2,inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g. PKCa,PKCb, PKCg), inhibitors of fatty acid synthetase, inhibitors of serinepalmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105,Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostainreceptors (e.g. SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulatorsof PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 familyincluding IL1 beta, modulators of RXRalpha. In addition suitableanti-diabetic agents include mechanisms listed by Carpino, P. A.,Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.

Suitable anti-obesity agents (some of which may also act asanti-diabetic agents as well) include 11β-hydroxy steroiddehydrogenase-1 (11β-HSD type 1) inhibitors, stearoyl-CoA desaturase-1(SCD-1) inhibitor, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists,monoamine reuptake inhibitors (such as sibutramine), sympathomimeticagents, β₃ adrenergic agonists, dopamine agonists (such asbromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists,melanin concentrating hormone antagonists, leptin (the OB protein),leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors(such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such asa bombesin agonist), neuropeptide-Y antagonists (e.g., NPY Y5antagonists such as velneperit), PYY₃₋₃₆ (including analogs thereof),BRS3 modulator, mixed antagonists of opiod receptor subtypes,thyromimetic agents, dehydroepiandrosterone or an analog thereof,glucocorticoid agonists or antagonists, orexin antagonists,glucagon-like peptide-1 agonists, ciliary neurotrophic factors (such asAxokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y.and Procter & Gamble Company, Cincinnati, Ohio), human agouti-relatedprotein (AGRP) inhibitors, histamine 3 antagonists or inverse agonists,neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTPinhibitors, such as dirlotapide, JTT130, Usistapide, SLx4090), opioidantagonist, mu opioid receptor modulators, including but not limited toGSK1521498, MetAp2 inhibitors, including but not limited to ZGN-433,agents with mixed modulatory activity at 2 or more of glucagon, GIP andGLP1 receptors, such as MAR-701 or ZP2929, norepinephrine transporterinhibitors, cannabinoid-1-receptor antagonist/inverse agonists, ghrelinagonists/antagonists, oxyntomodulin and analogs, monoamine uptakeinhibitors, such as but not limited to tesofensine, an orexinantagonist, combination agents (such as bupropion plus zonisamide,pramlintide plus metreleptin, bupropion plus naltrexone, phentermineplus topiramate), and the like.

Preferred anti-obesity agents for use in the combination aspects of thepresent invention include gut-selective MTP inhibitors (e.g.,dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) andCAS No. 913541-47-6), CCKa agonists (e.g.,N-benzyl-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamidedescribed in PCT Publication No. WO 2005/116034 or US Publication No.2005-0267100 A1), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g.,compounds described in U.S. Pat. No. 6,818,658), lipase inhibitor (e.g.,Cetilistat), PYY₃₋₃₆ (as used herein “PYY₃₋₃₆” includes analogs, such aspeglated PYY₃₋₃₆ e.g., those described in US Publication 2006/0178501),opioid antagonists (e.g., naltrexone), oleoyl-estrone (CAS No.180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensine(NS2330), leptin, bromocriptine, orlistat, AOD-9604 (CAS No.221231-10-3) and sibutramine. Preferably, compounds of the presentinvention and combination therapies are administered in conjunction withexercise and a sensible diet.

All of the recited U.S. patents and publications (including alltechnical bulletins referenced in the Examples) are incorporated hereinby reference in their entireties.

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are: n-BuLi for n-butyllithium; DMAP for4-dimethylaminopyridine; DME for dimethoxyethane; DMF forN,N-dimethylformamide; EtOAc for ethyl acetate; LAH for lithium aluminumhydride; MeOH for methanol; TFA for trifluoroacetic acid; and THF fortetrahydrofuran.

The present invention encompasses compounds of Formula (I), (II), (III),(IV), (V), (VI), (VII), (VIII), and (IX) when prepared by syntheticprocesses or by metabolic processes. Preparation of the compounds of theinvention by metabolic processes include those occurring in the human oranimal body (in vivo) or processes occurring in vitro.

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Aldrich Chemicals (Milwaukee, Wis.) or are readilyprepared using methods well known to those skilled in the art (e.g.,prepared by methods generally described in Louis F. Fieser and MaryFieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York(1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin, including supplements (also available viathe Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as intermediates for preparing compounds of the presentinvention. For a more detailed description of the individual reactionsteps, see the Examples section below. Those skilled in the art willappreciate that other synthetic routes may be used to synthesize theinventive compounds. Although specific starting materials and reagentsare depicted in the schemes and discussed below, other startingmaterials and reagents can be substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

In the preparation of compounds of the present invention protection ofremote functionalities such as carboxylic acids, amines, and/or hydroxygroups of intermediates may be necessary. The need for such protectionwill vary depending on the nature of the remote functionality and theconditions of the preparation methods. Suitable amino-protecting groups(NH-PG) include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc).Similarly, a “hydroxy-protecting group” refers to a substituent of ahydroxy group that blocks or protects the hydroxy functionality.Suitable hydroxyl-protecting groups (O-PG) include for example, allyl,acetyl, silyl, benzyl, para-methoxybenzyl, trityl, and the like.Carboxylic acid protecting groups include alkyl esters such as methy,ethyl, propyl, and tert-butyl. The need for such protection is readilydetermined by one skilled in the art. For a general description ofprotecting groups and their use, see T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

Schemes 1 through 10 outline the general procedures useful for thepreparation of compounds of the present invention. It is to beunderstood, however, that the invention, as fully described herein andas recited in the claims, is not intended to be limited by the detailsof the following schemes or modes of preparation.

Indole acids of general formula 6, wherein R₂, R₃, R₄, and A are asdefined in Formula (I) of the Summary section herein, can be synthesizedas shown in Scheme 1. Indoles of general formula 1, wherein Z is Cl, Br,I, triflate, mesylate, or tosylate (purchased or prepared using similarsynthetic methodology as found in Chem. Rev. 2006, 106, 2875) can beformylated with reagents such as N,N-dimethylformiminium chloride(purchased or prepared in situ with dimethylformamide and an activatingagent such as phosphorus oxychloride or oxalyl chloride at temperaturesranging from −78° C. to 120° C.) to provide compounds of general formula2. Aryl and heteroaryl compounds of general formula 3 (Z is Cl, Br, I,triflate, mesylate, or tosylate), purchased or synthesized using knownmethods, can be activated to provide compounds of general formula 4,where M is boron, zinc, tin, magnesium, indium, or silicon, by using anappropriate activating reagent including, but not limited to,dialkoxyboranes, bisboron compounds, tributyltin halides,isopropylmagnesium halides, or zinc powder and salts. Compounds ofgeneral formula 2 and 4 can be coupled using a variety of palladium andnickel catalysts with a variety of ligands or with no ligands (such asPddppfCl₂, tetrakistriphenylphosphine palladium, palladium (II) acetate,Pd₂dba³ or the like) at temperatures ranging from 25° C. to 120° C. withconventional heat or with microwave heat for 15 minutes to 24 hours.Oxidation of compounds of general formula 5 to provide compounds ofgeneral formula 6 can be effected with sodium chlorite, potassiumpermanganate, or the like, often with a chloronium ion scavenger such as2-methyl-2-butene present.

Alternatively in Scheme 2, compounds of general formula 6, wherein R₂,R₃, R₄, and A are as defined in Formula (I) of the Summary sectionherein, can be prepared by changing the sequence of reactions disclosedin Scheme 1. Indoles of general formula 1 can be coupled to aryl orheteroaryl compounds of general formula 4 to provide indoles of generalformula 7 which can be formylated and oxidized as described in Scheme 1to provide indoles of general formula 6.

Indole acids of general formula 6, wherein R₂, R₃, R₄, and A are asdefined in Formula (I) of the Summary section herein, can be synthesizedas shown in Scheme 3. Compounds of general formula 1 and 4 can becoupled in an analogous manner as described in Scheme 1 to provideindoles of general formula 7. Indoles of general formula 7 can beacylated with a variety of reagents including, but not limited to,trichloroacetyl chloride or trifluoroacetic anhydride to provide indolesof general formula 8. Hydrolysis of the trihalomethane group can beeffected with an alkaline metal hydroxide (potassium hydroxide, sodiumhydroxide, lithium hydroxide) or a carbonate base (potassium carbonate,sodium carbonate, cesium carbonate) in aqueous solution to providecompounds of general formula 6.

Indoles of general formula 6, wherein R₂, R₃, R₄, and A are as definedin Formula (I) of the Summary section herein, can be synthesized asshown in Scheme 4. Nitro compounds of general formula 9, where Z is Cl,Br, I, triflate, mesylate, or tosylate, can be coupled with compounds ofgeneral formula 4 using analogous methods as described in Scheme 1 toprovide compounds of general formula 10. Nitro compounds of generalformula 10 can be treated with dimethylformamide-dimethylacetal followedby treatment with a reducing agent such as palladium and hydrogen, ironin acidic media, tin (II) chloride, or the like to provide indoles ofgeneral formula 7. Indoles of general formula 7 can be formulated andoxidized as described in Scheme 1 to provide indoles of general formula6.

Indoles of general formula 6, wherein R₂, R₃, R₄, and A are as definedin Formula (I) of the Summary section herein, can be synthesized asshown in Scheme 5. Indoles of general formula 11, where Z is Cl, Br, I,triflate, mesylate, or tosylate, can be treated with an alkyl-metalreagent of general formula 12, where M is boron, silicon, tin, zinc, orthe like in the presence of a metal catalyst (palladium or nickel basedreagents such as PddppfCl₂, palladium tetrakistriphenylphosphine,Pd₂dba₃, or palladium (II) acetate with ligands such astriphenylphosphine, tricyclohexylphosphine, and other trialkylphosphineand triarylphosphines) to provide indoles of general formula 5. Indolesof general formula 5 can be oxidized as described in Scheme 1 to providecompounds of general formula 6.

Indoles of general formula 6, wherein R₂, R₃, R₄, and A are as definedin Formula (I) of the Summary section herein, can be synthesized asshown in Scheme 6. Indoles of general formula 1, where Z is Cl, Br, I,triflate, mesylate, or tosylate, can be treated with an acylatingreagent such as trichloroacetylchloride or trifluoroacetic anhydride toprovide compounds of general formula 12. Compounds of general formula 12can be treated with an alcohol such as methanol, ethanol, isopropanol,tert-butanol, or benzyl alcohol in the presence of base such aspotassium carbonate, sodium carbonate, sodium hydride, sodium metal orthe like to provide esters of general formula 13. Esters of generalformula 13 can be treated with activating reagents including, but notlimited to, dialkoxyboranes, bisboronate compounds, tributyltin halides,isopropylmagnesium halides, or zinc powder and salts, and the like toprovide activated indoles of general formula 14, where M is boron, zinc,tin, magnesium, indium, or silicon. Compounds of general formula 3 and14 can be coupled to provide compounds of general formula 15 using avariety of palladium and nickel catalysts with a variety of ligands orwith no ligand (such as PddppfCl₂, tetrakistriphenylphosphine palladium,palladium (II) acetate, Pd₂dba₃, or others) at temperatures typicallyranging from 25° C. to 120° C. with conventional heat or with microwaveirradiation typically for 15 minutes to 24 hours. Compounds of generalformula 15 can be treated with aqueous basic reagents such as lithiumhydroxide, sodium hydroxide, or potassium hydroxide, in solvents such asmethanol, ethanol, isopropanol, dioxane, or tetrahydrofuran, attemperatures ranging from 25 to 100° C. to provide compounds of generalformula 6. When R is tert-butyl, reagents such as hydrochloric acid ortrifluoroacetic acid can be used to effect hydrolysis and providecompounds of general formula 6.

Indoles of general formula 6, wherein R₂, R₃, R₄, and A are as definedin Formula (I) of the Summary section herein, can be synthesized asshown in Scheme 7. Indoles of general formula 12, where Z is Cl, Br, I,triflate, mesylate, or tosylate, can be treated with aqueous base suchas lithium hydroxide, sodium hydroxide, or potassium hydroxide insolvents such as dioxane, 1,2-dimethoxyethane, tetrahydrofuran,diethylether, or dichloromethane at temperatures ranging from 0° C. to100° C. to provide indole acids of general formula 16. Compounds ofgeneral formula 16 can be coupled to compounds of general formula 4 toprovide compounds of general formula 6 using the conditions/reagentsdescribed in Schemes 1-6.

Indoles of general formula 6, wherein R₂, R₃, R₄, and A are as definedin Formula (I) of the Summary section herein, can be synthesized asshown in Scheme 8. Indoles of general formula 1, where Z is Cl, Br, I,triflate, mesylate, or tosylate, can be treated with dialkoxyboranes,bisboronate compounds, tributyltin halides, isopropylmagnesium halides,zinc powder and salts, or the like to provide activated indoles ofgeneral formula 17, where M is boron, zinc, tin, magnesium, indium, orsilicon. Indoles of general formula 17 can be formylated, coupled tocompounds of general formula 3 (Z is Cl, Br, I, triflate, mesylate, ortosylate), and oxidized using conditions/reagents as described inSchemes 1-7 to provide compounds of general formula 6.

Indoles of general formula 6, wherein R₂, R₃, R₄, and A are as definedin Formula (I) of the Summary section herein, can be synthesized asshown in Scheme 9. Indoles of general formula 2, where Z is Cl, Br, I,triflate, mesylate, or tosylate, can be treated under conditionsdescribed in Scheme 6 to provide activated indoles of general formula18. Compounds of general formula 18 and 3 can be treated to couplingconditions as described in Scheme 1 and then oxidized as described inScheme 1 to provide indoles of general formula 6.

Indoles of general formula 22, wherein R₂, R₃, R₄, and A are as definedin Formula (I) of the Summary section herein, can be synthesized asshown in Scheme 10. Indoles of general formula 13, where Z is Cl, Br, I,triflate, mesylate, or tosylate, can be treated with a nitrogenprotecting reagent in the presence of N,N-dimethyl-4-aminopyridine and abase (triethylamine or diisopropylethylamine) to provide indoles ofgeneral formula 18, where PG is a nitrogen protecting group thatincludes, but is not limited to, tert-butyloxycarbonyl,benzyloxycarbonyl, ethyloxycarbonyl, or other carbamate formingprotecting groups, acetate, pivaloyl, or other amides,tert-butyldimethylsilane, triisopropylsilane, or other silicon-basedprotecting groups. Protected indoles of general formula 18 can becoupled with compounds of general formula 19 using conditions/reagentsdescribed in Schemes 1-8 to provide indoles of general formula 20.Compounds of general formula 20 can be alkylated under Mitsunobuconditions by treatment with an alcohol, an azodicarboxylate including,but not limited to diethyl azodicarboxylate, diisopropylazodicarboxylate, di-t-butyl azodicarboxylate, or di-2-methoxyethylazodicarboxylate, and a trialkyl or triarylphosphine including, but notlimited to, tributylphosphine or triphenylphosphine (on polymer-supportor in solution) in solvents such as THF, dioxane, or1,2-di-methoxyethane at temperatures from 25° C. to 100° C. to providecompounds of general formula 21. Alternatively, compounds of generalformula 20 can be alkylated by treatment with alkylating reagents in thepresence of a base (sodium hydride, potassium hydride, lithiumhydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate,triethylamine, or diisopropylethylamine) to provide compounds of generalformula 21. Compounds of general formula 21 can be treated underhydrolysis conditions as described in Scheme 7 to provide indoles ofgeneral formula 22.

Indazoles of general formula 26, wherein R₂, R₃, R₄, and A are asdefined in Formula (I) of the Summary section herein, can be synthesizedas shown above in Scheme 11. Commercially available isatins of generalformula 23 can be treated with a halogenating reagent such as such asbromine, N-bromosuccinimide, pyridinium tribromide, iodine,N-iodosuccinimide, chlorine, N-chlorosuccinimide, or the like in avariety of solvents including dimethylformamide to provide halogenatedindazoles of general formula 24. A four-step synthetic sequence can bethen be conducted, similar to the procedures found in Synth. Comm. 2005,35, 2681-2684, to provide indazoles of general formula 25. These foursteps can be executed in one sequence or done step-by-step withisolation after each step at temperatures ranging from 0° C. to ambienttemperature. Indazoles of general formula 25 can be coupled to compoundsof general formula 4, where M is boron, zinc, tin, magnesium, indium, orsilicon, using the procedures described in Scheme 1 to provide indazolesof general formula 26.

Indazoles of general formula 26, wherein R₂, R₃, R₄, and A are asdefined in Formula (I) of the Summary section herein, can be synthesizedas shown above in Scheme 12. Commercially available Indazoles of generalformula 27 can be treated with protecting reagents such astrimethylsilyloxyethoxymethyl chloride (SEM) or the like to provideIndazoles of general formula 28. Introduction of an ester group at the3-position can be effected by treatment with a metalating reagent suchas n-butyl lithium, t-butyl lithium, s-butyl lithium, or the likefollowed by introduction of reagents such as ethyl chloroformate, carbondioxide, or other carbon dioxide generating reagents to provideindazoles of general formula 29. Compounds of general formula 29 can becoupled with compounds of general formula 4 using procedures asdescribed in Scheme 1 to provide indazoles of general formula 30.Deprotection of the protecting group can be performed with a variety ofboth acidic and basic reagents such as hydrogen chloride in methanol,ethanol, or other solvents, tetrabutylammonium fluoride, sodiummethoxide, sodium ethoxide, or the like to provide indazoles of generalformula 31. Hydrolysis of the ester can be performed in a similar manneras described in Scheme 6 to provide indazoles of general formula 26.

Indazoles of general formula 26, wherein R₂, R₃, R₄, and A are asdefined in Formula (I) of the Summary section herein, can be synthesizedas shown above in Scheme 13. Indazoles of general formula 27 can becoupled with compounds of general formula 4 as described in Scheme 1 toprovide indazoles of general formula 32. Halogenation at the 3-positionof indazoles can be effected by treatment with a halogen source such asbromine, N-bromosuccinimide, pyridinium tribromide, iodine,N-iodosuccinimide, chlorine, N-chlorosuccinimide, or the like, in thepresence of a base such as sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydroxide, potassium hydroxide, or sodium hydride in avariety of solvents including dimethylformamide to provide halides ofgeneral formula 33. The halides of general formula 33 can be treatedwith a palladium catalyst such as tetrakistriphenyl phosphine palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PddppfCl₂),tris(dibenzylideneacetone)dipalladium(0) (Pd₂dba₃), or palladium (II)acetate with a variety of ligands such as triaryl (triphenylphosphine)and trialkylphoshines (dppf) in a solvent or solvent mixture containingalcohol solvents such as methanol, ethanol, isopropanol, or benzylalcohol, in the presence of an inorganic or organic base such as sodiumcarbonate, potassium carbonate, cesium carbonate, potassium acetate,sodium acetate, triethylamine, diisopropylethylamine, or the like in anatmosphere of carbon monoxide or a carbon monoxide containing sourcesuch as molybdenum hexacarbonyl to provide indazoles of general formula31. Esters of general formula 31 can be hydrolized as described inScheme 6 to provide indazoles of general formula 26.

Indole-3-sulfonic acids of general formula 34 wherein R₂, R₃, R₄, and Aare as defined in Formula (I) of the Summary section herein, can besynthesized as shown in Scheme 14. Indoles of general formula 7 can betreated with a sulfur trioxide source including, but not limited to,sulfur trioxide-pyridine, chlorosulfuric acid, sulfur trioxide (g), orsulfuric acid in the presence of acetic anhydride, or the like, toprovide indole-3-sulfonic acids of general formula 34.

EXAMPLES Example 16-Chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carboxylic acid

Step 1 5-bromo-6-chloro-1H-indole-3-carbaldehyde

A round-bottom flask was charged with DMF (54 mL). Phosphorusoxychloride (6.21 mL, 66.8 mmol) was added dropwise over 5 minutes, andthe reaction mixture was stirred at room temperature for an additional 5minutes. A solution of 5-bromo-6-chloro-1H-indole (7700 mg, 33.41 mmol)in DMF (7 mL) was added dropwise to the reaction mixture, which caused aprecipitate to form. The reaction mixture was then heated to 95° C. for25 minutes. The reaction mixture was treated with 1 N aqueous sodiumhydroxide (170 mL) and water (170 mL). The reaction mixture was stirredat 95° C. for 11 minutes. The reaction mixture was cooled to 0° C., andthe solids were collected by filtration. The solids were washed withwater (50 mL) and diethyl ether (50 mL) and dried in vacuo for 16 hoursat 65° C. to afford the title compound (7.77 g, 90%) as a tan solid. MS(AP+) 257.9 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.93 (s, 1H), 8.40 (s,1H), 8.38 (s, 1H), 7.80 (s, 1H).

Step 2 1-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)cyclobutanol

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (16.50g, 48.33 mmol), oven dried potassium acetate (20.03 g, 204.1 mmol), and1-(4-bromophenyl)cyclobutanol (10.00 g, 44.03 mmol) in 1,4-dioxane (120mL) was degassed with N₂ for 15 min, then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.44 g,2.99 mmol). The reaction mixture was heated to 110° C. and stirred for 2hours under N₂. The reaction mixture was cooled to room temperature andfiltered through celite, eluting with EtOAc. The filtrate was evaporatedto give a black oil, which was purified by flash chromatography (0-50%EtOAc/Heptane) three times to afford the title compound (8.68 g, 76%) asa white solid. GC/MS: 259. ¹H NMR (400 MHz, CD₃Cl) δ 7.83 (d, J=8.05 Hz,2H), 7.50 (d, J=8.29 Hz, 2H), 3.78 (s, 4H), 2.65-2.52 (m, 2H), 2.38-2.42(m, 2H), 1.98-2.03 (m, 1H), 1.72-1.80 (m, 1H), 1.03 (s, 6H).

Step 36-Chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carbaldehyde

A mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (6.15 g, 23.8mmol), 1-[4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-cyclobutanol(8.35 g, 32.1 mmol), 2 M aqueous potassium carbonate (47.5 mL, 95.0mmol) in EtOH (33 mL) and toluene (86 mL) was degassed with N₂ for 25minutes, then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.93 g,2.64 mmol). The reaction mixture was heated to 110° C. and stirred for 2hours. The reaction mixture was cooled to room temperature, poured intoa 3:1 mixture of saturated aqueous NH₄Cl solution/water (450 mL) andextracted with EtOAc (10×150 mL), followed by 9:1 CH₂Cl₂/i-PrOH (4×100mL). The combined organic layers were dried over Na₂SO₄ and concentratedin vacuo. The crude material was purified by flash chromatography(0-100% EtOAc/heptane, with 0.03% formic acid modifier) to afford thetitle compound (4.98 g, 64%) as a red solid. MS (ES+) 326.5 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 12.21 (br. s., 1H), 9.91 (s, 1H), 8.35 (s, 1H),8.02 (s, 1H), 7.67 (s, 1H), 7.54 (d, J=8.00 Hz, 2H), 7.38 (d, J=8.20 Hz,2H), 5.50 (s, 1H), 2.36-2.45 (m, 2H), 2.22-2.33 (m, 2H), 1.92 (m, 1H),1.61-1.71 (m, 1H).

Step 4 6-Chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carboxylicacid

To a solution of6-chloro-5-[4-(1-hydroxy-cyclobutyl)-phenyl]-1H-indole-3-carbaldehyde(4.88 g, 15.0 mmol) in MeCN (212 mL) and tert-butanol (212 mL) at 0° C.was added 2-methyl-2-butene (120 mL, 1.15 mol), followed by a solutionof sodium chlorite (25.5 g, 300 mmol) and sodium phosphate monobasichydrate (42.5 g, 308 mmol) in water (212 mL) dropwise via additionfunnel. The ice bath was removed and the reaction mixture was stirredvigorously at room temperature. After 13 hours, additional2-methyl-2-butene (50 mL, 480 mmol) was added, followed by sodiumchlorite (10.6 g, 125 mmol) and sodium phosphate monobasic hydrate (17.7g, 125 mmol) as solids. The reaction mixture was stirred at roomtemperature for an additional 5 hours, and treated with additional2-methyl-2-butene (25 mL, 240 mmol), solid sodium chlorite (5.3 g, 73mmol) and solid sodium phosphate monobasic hydrate (8.8 g, 73 mmol).After an additional 4 hours, the reaction mixture was poured into a 4:1mixture of saturated aqueous NH₄Cl solution/water (500 mL), andextracted with EtOAc (3×400 mL). The combined organic layers were driedover Na₂SO₄ and concentrated in vacuo. The resulting material was loadedonto a silica gel plug and eluted, first with heptane/EtOAc (4:1, 1.5L), followed by 1:4 heptane/EtOAc (3 L) then EtOAc (1 L). The filtratesfrom the second and third elutions were combined and concentrated invacuo. The resulting tan solid was partially dissolved in 4:1 DMF/DCM,loaded onto an Isco silica gel cartridge, and purified by flashchromatography (20-80% EtOAc/heptane, with 0.2% formic acid modifier) togive the title compound (3.65 g, 71%) as a white solid. MS (ES+) 340.2(M−H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.10 (s, 1H), 11.95 (s, 1H), 8.08(s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.57 (d, J=7.1 Hz, 2H), 7.41 (d,J=7.1 Hz, 2H), 5.52 (s, 1H), 2.48-2.40 (m, 2H), 2.35-2.26 (m, 2H),1.97-1.90 (m, 1H), 1.76-1.62 (m, 1H).

Alternatively, Example 1 may be prepared as follows:

Example 1 Step 1 methyl 5-bromo-6-chloro-1H-indole-3-carboxylate

To a stirred mixture of 5-bromo-6-chloro-1H-indole (60 g, 260 mmol),N,N-dimethylaminopyridine (3.21 g, 26.0 mmol), pyridine (56.5 mL, 703mmol), and tetrahydrofuran (400 mL) was added in drops at 0° C. neattrichloroacetyl chloride (70.1 mL, 625 mmol). The obtained mixture waswarmed to room temperature in 2 h (a precipitate began to form) and wasstirred at room temperature for 3 days. Added in drops 110 ml ofmethanol at 0-10° C. followed by 70 ml of 25% sodium methoxide inmethanol (680 mmol) at 0° C. The mixture was then stirred at 45° C. for3 h. Then 250 ml of water and 200 ml of MTBE were added. The organicextract was separated, washed with brine, dried over magnesium sulfate,and concentrated at 50° C. and 90 mm Hg to ˜1/4 of the initial volume.Precipitate was filtered off, washed with MTBE, and dried in vacuum at45° C. to obtain the title compound (39.9 g, 53% yield). The motherliquor was concentrated to a heavy slurry. Methanol (400 ml) was addedand the mixture was stirred at 65° C. for 4 h and slowly cooled to roomtemperature and stirred overnight. The solid was filtered off, washedwith methanol, and dried in vacuo at 45° C. to obtain additional titlecompound (16.88 g, 22%). Total yield=75%. MS (ES−): 288.0, 290.0 (M+H)⁺¹H NMR (500 MHz, DMSO-d₆) ppm 12.17 (br. s, 1H), 8.26 (s, 1H), 8.18 (s,1H), 7.74 (s, 1H), 3.82 (s, 3H).

Step 2 methyl6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylate

A round bottomed flask was charged with[4-(1-hydroxycyclobutyl)phenyl]boronic acid (104.0 g, 541.6 mmol),methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (142.0 g, 492.1 mmol),bis(triphenylphosphine)dichloropalladium (7.0 g, 10 mmol), potassiumcarbonate solution (183 g, 1.32 mol in 550 mL water), and2-methyltetrahydrofuran (1.000 L). The mixture was then degassed bybubbling nitrogen gas through the solution for 30 minutes at roomtemperature with stirring. The mixture was then stirred at 75° C.(internal temperature) for 18 h. The mixture was cooled to roomtemperature under stirring and 300 ml of heptane was added and theaqueous phase was separated and discarded. Brine (300 ml) was added,stirred at room temperature for 10 min, then the aqueous layer wasseparated and discarded. The organic phase was stirred at 70° C. andslowly 1400 ml of heptane was added via addition funnel with stirring. Aprecipitate began to form after first 600 ml was added. Continuedstirring at 70° C. for 30 min and cooled to room temperature in 2.5 h.The solid was filtered off, washed with water, and2-methyltetrahydrofuran/heptane (1:2, 400 ml), dried on the filterduring 2 h to obtain crude product. The crude product was stirred in1300 ml of methanol at 62° C. (internal temperature, gentle reflux) for8 h and then cooled to room temperature in 3 h and stirred at roomtemperature overnight. The solid was collected via filtration to obtainthe 135 g of material. This material was then dissolved in 900 mLtetrahydrofuran at 60° C. Heptane (300 ml) and silica gel (64 g) wereadded and the mixture was cooled to room temperature under stirringduring 2.5 h. The mixture was filtered through a pad of silica gel andthe filter cake was washed with tetrahydrofuran-heptane (3:1) and thefiltrate concentrated to dryness. Methanol (500 ml) was added to theresidue and the slurry was concentrated again to dryness to obtain thetitle compound as an off-white solid (131.0 g, 368.0 mmol, 75% yield).MS (ES−): 354.4 (M−H)⁻ ¹H NMR (400 MHz, DMSO-d₆) ppm 12.08 (br. s, 1H),8.19 (d, 1H), 7.94 (s, 1H), 7.67 (s, 1H), 7.58 (d, 2H), 7.40 (s, 2H),5.54 (s, 1H), 3.80 (s, 3H), 2.39-2.49 (m, 2H), 2.23-2.37 (m, 2H), 1.96(dt, 1H), 1.63-1.79 (m, 1H).

Step 3 6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylicacid

A round bottomed flask was charged with methyl6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylate (131g, 368 mmol), methanol (2.20 L), and sodium hydroxide (90.2 g, 2.21 molin 740 mL water) then stirred at 70° C. for 18 h. The reaction mixturewas cooled to room temperature, filtered through celite and the motherliquor was concentrated to ˜30% of the initial volume—no precipitateformed. Water (700 ml) was added. The clear tan solution was washed withMTBE (3×250 ml). The organic layers were discarded. To the stirredlight-cherry aqueous solution (total volume 1800 ml) at 18˜25 C withexternal cooling was added in drops 38% HCl (200 ml), to pH˜2-3 followedby addition of ethyl acetate in one portion (250 ml). After addition ofethyl acetate material began to solidify. To the stirring heterogeneousmixture 250 ml of heptane was slowly added via addition funnel at roomtemperature, and the mixture was stirred at room temperature for 4hours. The solid was filtered off, washed with water, washed with ethylacetate-heptane mixture (1:1), and dried on a filter at room temperatureand in vacuum oven at 50° C. to obtain light-yellow solid. To this solidwas then added 630 ml of tetrahydrofuran and was stirred at 65° C.(internal temperature) for 4 hours, then slowly 630 ml of ethyl acetatewas added from a dropping funnel, and the resulting slurry was slowlycooled under stirring to room temperature overnight. Solid was filteredoff, washed with tetrahydrofuran-ethyl acetate (1:1), and dried invacuum at 50° C. to obtain 107.0 g of solid. The mother liquor wasconcentrated and the residue was washed with acetone, filtered off, anddried to obtain an additional 12.5 g of solid. This solid was thendissolved in 800 ml of ethanol (containing 0.3 ml of 1 M aqueous NaOH)at 60° C. and 800 ml of water was added slowly via addition funnel understirring at 55-60° C. In the end of the addition of water a precipitatebegan to form. The suspension was stirred at 60° C. for 2 h, then at 40°C. for 24 h and at room temperature for 40 hours. The solid was filteredoff, washed with ethanol-water (1:1), and dried in vacuum at 50° C. toobtain the title compound as a crystalline off-white solid (72.4 g, 58%yield). The mother liquor was concentrated to ˜30% of the initial volumeand precipitate formed. It was filtered off and dried in vacuo to obtainadditional batch of the title compound (14.5 g, 12% yield). Totalyield=70%. MS (ES−): 340.3 (M−H)⁻ ¹H NMR (400 MHz, DMSO-d₆) ppm 12.12(s, 1H) 11.95 (br. s., 1H) 8.09 (d, 1H) 7.96 (s, 1H) 7.65 (s, 1H) 7.58(d, 2H) 7.42 (d, 2H) 5.53 (s, 1H) 2.48-2.42 (m, 2H) 2.32 (m, 2H) 1.96(tq, 1H) 1.62-1.79 (m, 1H).

Example 2 6-Chloro-5-[4-(hydroxymethyl)phenyl]-1H-indole-3-carboxylicacid

Step 1 6-Chloro-5-(4-hydroxymethyl-phenyl)-1H-indole-3-carbaldehyde

A mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (783 mg, 3.03mmol), 4-(hydroxymethyl)benzene boronic acid (460 mg, 3.03 mmol), 2 Naqueous potassium carbonate (6.4 mL, 13 mmol) in toluene (9 mL) and EtOH(13 mL) was degassed with N₂ for 5 minutes, then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (247 mg,0.30 mmol). The mixture was heated in a sealed tube to 120° C. andstirred for 2.5 hours. The reaction mixture was cooled to roomtemperature, diluted with EtOAc (200 mL), then washed with water (50 mL)and brine (50 mL). The organic layer was dried over MgSO₄ andconcentrated in vacuo. The resulting brown foam was purified by flashchromatography (20-100% EtOAc/heptane) to afford a pale yellow solid.The solid was dissolved in 5:1 EtOAc/heptane (30 mL), and a colorlessprecipitate formed. The precipitate was collected by filtration, washedwith heptane and dried under vacuum to afford the title compound (173mg, 20% yield) as a colorless solid. MS (ES+) 286.0 (M+H)⁺. ¹H NMR (500MHz, CD₃OD) δ 9.92 (s, 1H) 8.07 (s, 1H) 8.25 (s, 1H) 7.64 (s, 1H) 7.44(m, 4H) 4.70 (s, 2H).

Step 2 6-Chloro-5-[4-(hydroxymethyl)phenyl]-1H-indole-3-carboxylic acid

To a solution of6-chloro-5-(4-hydroxymethyl-phenyl)-1H-indole-3-carbaldehyde (422 mg,1.48 mmol) in MeCN (18 mL), tert-butanol (18 mL) and 2-methyl-2-butene(12 mL, 110 mmol) at 0° C. was added a solution of sodium chlorite (1.25g, 14.8 mmol) and sodium phosphate monobasic hydrate (2.04 g, 14.8 mmol)in water (9 mL) dropwise. The ice bath was removed and the solution wasstirred at room temperature. After 5 hours, additional 2-methyl-2-butene(3 mL, 27.5 mmol) was added, followed by sodium chlorite (1.25 g, 14.8mmol) and sodium phosphate monobasic hydrate (2.04 g, 14.8 mmol) inwater (9 mL) dropwise. The resulting solution was stirred at roomtemperature. After 27 hours total reaction time, the solution wasconcentrated in vacuo to afford a pale yellow solid. Water (5 mL) wasadded to the solid and the mixture was extracted with EtOAc (2×50 mL).The combined organic layers were concentrated in vacuo and purified byflash chromatography (35-90% EtOAc/heptane, with 0.2% formic acidmodifier) to afford a pale yellow solid. The solid was stirred in EtOAc(5 mL) at 55° C. for 6 hours, and the resulting slurry was cooled toroom temperature. The precipitate was filtered and washed with EtOAc (1mL) to afford the title compound (182 mg, 41% yield) as a cream-coloredcrystalline solid. MS (ES+) 300.0 (M−H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.00(s, 1H) 7.98 (s, 1H) 7.56 (s, 1H) 7.40 (m, 4H) 4.65 (s, 2H).

Example 3 6-Chloro-5-phenyl-1H-indole-3-carboxylic acid

Step 1 6-Chloro-5-phenyl-1H-indole-3-carbaldehyde

A mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (200 mg, 0.77mmol), phenyl boronic acid (114 mg, 0.93 mmol), 2 N aqueous potassiumcarbonate (1.15 mL, 3.10 mmol) in toluene (3.3 mL) and EtOH (1.1 mL) wasdegassed with N₂, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (56.6 mg,0.077 mmol), and degassed again with N₂. The mixture was subjected tomicrowave irradiation conditions at 120° C. for 30 minutes. The reactionmixture was cooled to room temperature, diluted with water and extractedwith EtOAc (50 mL). The organic layer was washed with brine, dried overMgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography (0-46% EtOAc/petroleum ether) to afford the titlecompound (190 mg, 98% yield) as a yellow solid.

MS (ES+) 255.9 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.91 (s, 1H), 8.18 (s,1H), 8.13 (s, 1H), 7.63 (s, 1H), 7.44-7.36 (m, 5H).

Step 2 6-Chloro-5-phenyl-1H-indole-3-carboxylic acid

To a solution of 6-chloro-5-phenyl-1H-indole-3-carbaldehyde (90 mg, 0.35mmol) in MeCN (4 mL), tert-butanol (4 mL) and 2-methyl-2-butene (4 mL,27.5 mmol) at 0° C. was added a solution of sodium chlorite (327 mg,4.88 mmol) and sodium phosphate monobasic hydrate (761 mg, 4.88 mmol) inwater (4 mL) dropwise. The ice bath was removed and the solution wasstirred at room temperature. After 6 hours, additional sodium chlorite(327 mg, 4.88 mmol) and sodium phosphate monobasic hydrate (761 mg, 4.88mmol) were added as solids and the resulting solution was stirred atroom temperature for an additional 14 hours. The reaction mixture wasconcentrated in vacuo and the aqueous residue was extracted with EtOAc(30 mL). The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by reverse phaseHPLC to afford the title compound (30.0 mg, 31%) as a white solid. MS(ES+) 271.9 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.13 (br. s., 1H),11.96 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.48-7.38 (m,5H).

Example 46-Fluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carboxylic acid

Step 11-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol

To a solution of 1-(4-bromophenyl)cyclobutanol (325 mg, 1.43 mmol) and5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (437 mg, 1.72 mmol)in anhydrous THF (20 mL) was added potassium acetate (425 mg, 4.33 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40.0mg, 0.055 mmol). The reaction mixture was degassed with N₂ for 3minutes, and heated to reflux under N₂ for 16 hours. The reactionmixture was cooled to room temperature, filtered and washed withpetroleum ether (30 mL). The filtrate was concentrated in vacuo, andpurified by flash chromatography (9-20% EtOAc/petroleum ether) to affordthe title compound (279.0 mg, 71%) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.76 (d, J=8.00 Hz, 2H), 7.44 (d, J=8.40 Hz, 2H), 2.49 (m, 2H),2.30 (m, 2H), 1.92 (m, 1H), 1.63 (m, 1H), 1.278 (s, 12H).

Step 26-Fluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carbaldehyde

A mixture of 5-bromo-6-fluoro-1H-indole-3-carbaldehyde (90 mg, 0.37mmol),1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol(120 mg, 0.44 mmol), 2 N aqueous potassium carbonate (0.75 mL, 1.49mmol) in toluene (3.0 mL) and EtOH (1.0 mL) was degassed with N₂ for 3minutes, and treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30.0 mg,0.041 mmol). The mixture was subjected to microwave irradiationconditions at 110° C. for 2 hours. The reaction mixture was cooled toroom temperature, poured into half-saturated aqueous NH₄Cl solution (15mL) and extracted with EtOAc (6×15 mL). The combined organic layer werewashed with brine, dried over MgSO₄ and concentrated in vacuo. The crudematerial was purified by flash chromatography (9-50% EtOAc/petroleumether) to afford the title compound (58.0 mg, 51% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.0 (s, 1H), 8.42 (s, 1H), 8.20 (d,J=8.00 Hz, 1H), 7.66 (d, J=8.40 Hz, 2H), 7.59 (d, J=8.40 Hz, 2H), 7.50(d, J=10.80 Hz, 1H), 2.48 (m, 2H), 2.41 (m, 2H), 2.02 (m, 1H), 1.76 (m,1H).

Step 3 6-Fluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carboxylicacid

To a solution of 6-fluoro-5-phenyl-1H-indole-3-carbaldehyde (58.0 mg,0.19 mmol) in MeCN (3 mL), tert-butanol (3 mL) and 2-methyl-2-butene (2mL, 13.7 mmol) at 0° C. was added a solution of sodium chlorite (253.0mg, 3.75 mmol) and sodium phosphate monobasic hydrate (585.0 mg, 3.75mmol) in water (1.5 mL) dropwise. The ice bath was removed and thesolution was stirred at room temperature for 16 hours. The reactionmixture was concentrated in vacuo and the aqueous residue was extractedwith EtOAc (3×15 mL). The organic layer was washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The crude material was purifiedby prep-HPLC (Boston Symmetrix ODS-H 150*30 mm*5 μm; 26-46% MeCN inwater (0.225% formic acid); flow rate: 30 mL/min) to afford the titlecompound (9.5 mg, 16%) as a white solid. MS (ES+) 324.1 (M−H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 12.13 (br.s., 1H), 11.95 (s, 1H), 8.04-8.06 (m,2H), 7.60 (d, J=8.40 Hz, 2H), 7.53 (d, J=6.80 Hz, 2H), 7.38 (d, J=11.20Hz, 1H), 5.56 (s, 1H), 2.42-2.49 (m, 2H), 2.29-2.36 (m, 2H), 1.93-1.98(m, 1H), 1.68-1.73 (m, 1H).

Example 56-Chloro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-1H-indole-3-carboxylic acid

Step 16-chloro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-1H-indole-3-carbaldehyde

A mixture of 5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl](149.0 mg, 0.44 mmol), oven dried potassium acetate (173.0 mg, 1.75mmol) and 3-(4-bromo-phenyl)-oxetan-3-ol (100.0 mg, 0.44 mmol) in1,4-dioxane (2 mL) was degassed with N₂ for 5 minutes, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.0 mg,0.044 mmol) and subjected to microwave irradiation at 110° C. for 1hour. The cooled reaction mixture was filtered through celite andconcentrated in vacuo to give a black oil. To the dark oil was added5-bromo-6-chloro-1H-indole-3-carbaldehyde (112.0 mg, 0.43 mmol), 2 Naqueous potassium carbonate (0.4 mL, 0.80 mmol), toluene (1.5 mL) andEtOH (0.5 mL). The reaction mixture was degassed with N₂ for 10 minutes,treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(25.0 mg, 0.034 mmol), and heated in a pressure tube to 110° C. for 2hours. The cooled reaction mixture was purified by flash chromatography(33-100% EtOAc/heptanes) to give a solid. The solid was triturated inMeOH and filtered to afford the title compound (50 mg, 35%) as a yellowsolid. MS (ES+) 328.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H),9.92 (s, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 7.66 (d, J=9.4 Hz, 2H), 7.44(d, J=8.2 Hz, 2H), 6.36 (s, 1H), 4.80-4.76 (m, 2H), 4.75-4.71 (m, 2H).

Step 26-Chloro-5-(4-(3-hydroxyoxetan-3-yl)phenyl)-1H-indole-3-carboxylic acid

To the mixture of6-chloro-5-[4-(3-hydroxy-oxetan-3-yl)-phenyl]-1H-indole-3-carbaldehyde(50.0 mg, 0.15 mmol) in MeCN (2 mL) was added 2-methyl-2-butene (2.0 mL,13.7 mmol), followed by sodium chlorite (138 mg, 1.53 mmol) and sodiumphosphate monobasic hydrate (211.0 mg, 1.53 mmol) in water (1 mL). Thereaction mixture was stirred at room temperature for 20 hours, andconcentrated in vacuo. The residue was acidified with 1 N aqueous citricacid (1 mL) and extracted with EtOAc. The organic layer was dried overMgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography (34-80% EtOAc/heptanes, with 0.2% formic acidmodifier) to afford the title compound (18 mg, 34%) as a brown solid. MS(ES−) 342.3 (M−H)⁻. ¹H NMR (400 MHz, CD₃OD) δ 8.02 (s, 1H), 7.98 (s,1H), 7.66 (d, J=8.20 Hz, 2H), 7.56 (s, 1H), 7.47 (d, J=8.20 Hz, 2H),4.87-4.80 (m, 4H).

Example 64,6-Difluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carboxylicacid

Step 1 4,6-difluoroinoline

To a suspension of 4,6-difluoro-1H-indole (5 g, 32.9 mmol) in drydichloromethane (100 mL) was added triethylsilane (10 g, 85.5 mmol) atroom temperature. The reaction was then cooled to 0° C. andtrifluoroacetic acid (50 mL) was added dropwise. The reaction wasstirred at room temperature for 4 hours. The mixture was poured intocold saturated aqueous sodium bicarbonate solution and diluted withdichloromethane (200 mL). The layers were separated and the organicphase was dried over sodium sulfate, concentrated in vacuo, and purifiedby silica chromatography to give the title compound (4.5 g, 90% yield)as colorless oil.

Step 2 5-bromo-4,6-difluoroinoline

To a solution of 4,6-difluoroindoline (4.6 g, 29.8 mmol) in acetonitrile(50 mL) was added a solution of N-bromosuccinimide (3.68 g, 20.6 mmol)acetonitrile (30 mL) at 0° C. dropwise. The reaction was stirred for 30minutes and quenched with saturated aqueous sodium bicarbonate solutionand diluted with ethyl acetate. The layers were separated and theorganic phases were dried over sodium sulfate, filtered and concentratedin vacuo. The residue was purified by flash chromatography (0-60% ethylacetate in petroleum ether) to give the title compound (4.0 g, 58%yield) as colorless oil

Step 3 5-bromo-4,6-difluoro-1H-indole

To a solution of 5-bromo-4,6-difluoroindoline (3.6 g, 15.4 mmol) inchloroform (150 mL) was added manganese dioxide (5.3 g, 61 mmol) at roomtemperature/. The mixture was heated to reflux temperature for 2 hoursthen cooled to room temperature. The reaction was filtered and thefiltrate was concentrated in vacuo. Flash column chromatography was thenused to provide the title compound (3.6 g, yield 100%) as brown solid.MS (ES+): 232.0 (M+H). ¹H NMR (CDCl₃, 400 MHz): δ 8.27 (br. s, 1H), 7.19(m, 1H), 7.02 (d, 1H), 6.61 (m, 1H).

Step 4 5-Bromo-4,6-difluoro-1H-indole-3-carbaldehyde

To a solution of 5-bromo-4,6-difluoro-1H-indole (1.29 g, 5.56 mmol) inacetonitrile (7.0 mL) was added N,N-dimethylformiminium chloride (1.07g, 8.34 mmol). The reaction mixture was stirred at room temperature for45 minutes. To the reaction mixture was added 1N NaOH (15 mL, 15 mmol).The resulting mixture was heated to 100° C. for 60 minutes, cooled to 0°C. and the resulting solid was collected via filtration, washed withwater, and air-dried with vacuum to provide 900 mg of the titlecompound. An additional crop of solids formed in the filtrate, wascollected, and dried to provide an additional 371 mg of the titlecompound for a total of 1.271 g (88% yield). MS (ES⁺) 260.3 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 12.58 (br. s, 1H), 9.93 (d, J=3.90 Hz, 2H),8.34 (s, 2H), 7.39 (dd, J=8.49, 1.07 Hz, 1H).

Step 54,6-Difluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carbaldehyde

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (188.0mg, 0.55 mmol), oven dried potassium acetate (230.0 mg, 2.34 mmol), and1-(4-bromophenyl)cyclobutanol (114.0 mg, 0.50 mmol) in 1,4-dioxane (2mL) was degassed with N₂ for 15 min, then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20.0 mg,0.027 mmol). The reaction mixture was subjected to microwave irradiationat 110° C. for 1 hour. The cooled reaction mixture was filtered throughcelite, rinsed with EtOAc and concentrated to dryness. To the resultingdark solid ((45.0 mg, 0.17 mmol) was added5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (45.0 mg, 0.17 mmol), 2 Naqueous potassium carbonate (0.20 mL, 0.40 mmol), toluene (1.5 mL) andEtOH (0.5 mL). The reaction mixture was degassed with N₂ for 10 minutes,treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(14.0 mg, 0.019 mmol), and heated in a sealed pressure tube at 110° C.for 2 hours. The reaction mixture was cooled to room temperature andpurified by flash chromatography (0-67% EtOAc/heptanes) to give thetitle compound (37 mg, 65%) as a white solid. MS (ES⁺) 328.0 (M+H)⁺. ¹HNMR (500 MHz, CD₃OD) δ 10.04 (d, J=2.68 Hz, 1H), 8.15 (s, 1H), 7.64 (d,J=8.05 Hz, 2H), 7.48 (d, J=8.05 Hz, 2H), 7.21 (d, J=9.51 Hz, 1H),2.57-2.66 (m, 2H), 2.39-2.46 (m, 2H), 2.03-2.12 (m, 1H), 1.73-1.83 (m,1H).

Step 64,6-Difluoro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indole-3-carboxylicacid

To a solution of4,6-difluoro-5-[4-(1-hydroxy-cyclobutyl)-phenyl]-1H-indole-3-carbaldehyde(37.0 mg, 0.11 mmol) in a mixture of MeCN (2 mL), tert-butanol (1 mL)and water (2 mL) was added sodium phosphate monobasic hydrate (214.0 mg,1.55 mmol), sodium chlorite (114.0 mg, 1.26 mmol) and 2-methyl-2-butene(1.0 mL, 6.85 mmol). The reaction mixture was stirred at roomtemperature for 24 hours, acidified with 1 N aqueous citric acidsolution (1 mL) and extracted with EtOAc. The organic layer was driedover MgSO₄ and concentrated in vacuo. The resulting yellow gum waspurified by reverse phase HPLC (Column: Waters XBridge C18 19×100, 5 μm;Mobile phase A: 0.03% NH₄OH in water (v/v); Mobile phase B: 0.03% NH₄OHin MeCN (v/v); 95.0% H₂O/5.0% MeCN linear to 60% H₂O/40% MeCN in 8.5min, 60% H₂O/40% MeCN linear to 0% H₂O/100% MeCN in 0.5 min, HOLD at 0%H₂O/100% MeCN to 10.0 min. Flow: 25 mL/min) to afford the title compound(9.4 mg, 24%).

MS (ES⁺) 344.1 (M+H)⁺. Retention time=2.48 minutes (Waters Atlantis dC184.6×50, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B:0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 7 6-fluoro-5-[4-(hydroxymethyl)phenyl]-1H-indole-3-carboxylicacid

Step 1 6-fluoro-5-[4-(hydroxymethyl)phenyl]-1H-indole-3-carbaldehyde

A mixture of 5-bromo-6-fluoro-1H-indole-3-carbaldehyde (100 mg, 0.413mmol), [4-(hydroxymethyl)phenyl]boronic acid (69 mg, 0.454 mmol),ethanol (1.04 mL), toluene (1.0 mL) and 2 M aqueous potassium carbonate(0.824 mL, 1.65 mmol) were deoxygenated with nitrogen.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (25 mg,0.033 mmol) was added and the reaction mixture was deoxygenated withnitrogen for 2 more minutes. The reaction mixture was sealed and heatedat 90° C. for 16 hours. After cooling to room temperature, the phaseswere separated, and the aqueous phase was diluted with water andextracted twice with ethyl acetate. The combined organic layers wereconcentrated in vacuo and purified using silica gel chromatography (1:3to 3:1 ethyl acetate/heptanes) to give the title compound (65 mg). MS(ES−) 268.2 (M−H)⁻.

Step 2 6-fluoro-5-[4-(hydroxymethyl)phenyl]-1H-indole-3-carboxylic acid

A solution of6-fluoro-5-[4-(hydroxymethyl)phenyl]-1H-indole-3-carbaldehyde (65 mg,0.24 mmol) in acetonitrile (3 mL) and tert-butanol (3 mL) was treatedwith 2-methyl-2-butene (2 mL, 18.4 mmol) and cooled to 0° C. A solutionof sodium chlorite (410 mg, 4.9 mmol) and sodium dihydrogen phosphatemonohydrate (684 mg, 4.96 mmol) in water (3 mL) was added dropwise viaan addition funnel. The reaction mixture was warmed to room temperatureand stirred for 65 hours. The reaction was partially evaporated invacuo, and partitioned between water and ethyl acetate. The organicphase was concentrated in vacuo. The crude material was purified usingreverse-phase chromatography to give the title compound (20.4 mg).

MS (ES+) 286.0 (M+H)⁺. Retention time: 2.2 min; Atlantis dC18 5 μm4.6×50 mm, 95% H₂O/5% MeCN linear to 5% H₂O/95% MeCN over 4.0 min, HOLDat 5% H₂O/95% MeCN to 5.0 min. (0.05% TFA).

Example 85-{4-[(1-acetylazetidin-3-yl)oxy]phenyl}-6-chloro-1H-indole-3-carboxylicacid

Step 1 tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate

A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (200 mg, 1.15mmol), 4-bromophenol (240 mg, 1.39 mmol), triphenylphosphine (398 mg,1.50 mmol) and DIAD (202 mg, 1.39 mmol) in anhydrous THF (5 mL) washeated to 110° C. and stirred under nitrogen for 5 hours. The reactionmixture was concentrated in vacuo to give a brown residue, which waspurified by flash chromatography (petroleum ether/ethyl acetate 10:1 to4:1) to give tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate (300mg, 79.5%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, 2H), 6.72 (d, 2H), 4.84 (m, 1H), 4.28(m, 2H), 3.99 (m, 2H), 1.44 (s, 9H).

Step 2 3-(4-bromophenoxy)azetidine

To a solution of tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate(300 mg, 0.90 mmol) in CH₂Cl₂ (5 mL) was added TFA (5 mL). The mixturewas stirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo to give 3-(4-bromophenoxy)azetidine (207 mg, 100%)as a yellow oil.

Step 3 1-[3-(4-bromophenoxy)azetidin-1-yl]ethanone

To a solution of 3-(4-bromophenoxy)azetidine (207 mg, 0.91 mmol) inCH₂Cl₂ (10 mL) was added triethylamine (276 mg, 2.73 mmol) and aceticanhydride (186 mg, 1.82 mmol). The mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuo togive a yellow oil. The crude product was diluted with ethyl acetate (20mL), washed with 1 N HCl and saturated NaHCO₃, dried over sodiumsulfate, and concentrated in vacuo to give1-[3-(4-bromophenoxy)azetidin-1-yl]ethanone (245 mg, 100%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, 2H), 6.61 (d, 2H),4.89 (m, 1H), 4.49 (m, 1H), 4.37 (m, 1H), 4.17 (m, 1H), 4.03 (m, 1H),1.90 (s, 3H).

Step 41-{3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]azetidin-1-yl}ethanone

To a solution of 1-[3-(4-bromophenoxy)azetidin-1-yl]ethanone (200 mg,0.74 mmol) in 1,4-dioxane (5 mL) was added5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (184 mg, 0.814 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (53 mg,0.074 mmol) and KOAc (363 mg, 3.71 mmol). The mixture was degassed withnitrogen for 3 min and heated to 110° C. by microwave irradiation for 1hour. The reaction mixture was concentrated in vacuo to give a residue,which was dissolved with ethyl acetate (50 mL) and washed with brine(2×15 mL). The organic layer was dried over sodium sulfate andconcentrated in vacuo to give a residue, which was purified by flashchromatography (petroleum ether/ethyl acetate=10:1 to 4:1) to give1-{3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]azetidin-1-yl}ethanone(130 mg, 58%) as a yellow solid.

Step 5[(1-acetylazetidin-3-yl)oxy]phenyl}-6-chloro-1H-indole-3-carbaldehyde

To a solution of1-{3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]azetidin-1-yl}ethanone(130 mg, 0.43 mmol) in toluene (5 mL) was added5-bromo-6-chloro-1H-indole-3-carbaldehyde (134 mg, 0.52 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (32 mg,0.045 mmol), and 2 M aqueous potassium carbonate (0.86 mL, 1.72 mmol)and ethanol (1.7 mL). The mixture was degassed with nitrogen for 3 minand heated to 110° C. by microwave irradiation for 1 h. The mixture wasconcentrated in vacuo to give a residue, which was dissolved with ethylacetate (50 mL) and washed with brine (2×15 mL). The organic layer wasdried over sodium sulfate and concentrated in vacuo to give a brownresidue, which was purified by flash chromatography (petroleumether/ethyl acetate=20:1 to 4:1) to give[(1-acetylazetidin-3-yl)oxy]phenyl}-6-chloro-1H-indole-3-carbaldehyde(70 mg, 44%) as a yellow solid.

Step 65-{4-[(1-acetylazetidin-3-yl)oxy]phenyl}-6-chloro-1H-indole-3-carboxylicacid

To a solution of[(1-acetylazetidin-3-yl)oxy]phenyl}-6-chloro-1H-indole-3-carbaldehyde(70 mg, 0.19 mmol) in acetonitrile (3 mL) was added tert-butanol (3 mL),water (3 mL), and 2-methyl-2-butene (1.56 mL). The solution was cooledto 0° C., and a solution of sodium chlorite (382 mg, 5.7 mmol) andsodium phosphate monobasic (787 mg, 5.7 mmol) in water (3 mL) was addeddropwise. After the addition was complete, the reaction mixture wasstirred at room temperature for 96 h. The reaction mixture was quenchedwith sodium sulfite and concentrated in vacuo to dryness and theresulted solid was washed with DMF. The filtrate was concentrated invacuo to give a brown residue, which was purified by prep-HPLC to give5-{4-[(1-acetylazetidin-3-yl)oxy]phenyl}-6-chloro-1H-indole-3-carboxylicacid (10 mg, 14%) as an off-white solid. MS (ES+) 384.8 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 7.62 (s,1H), 7.37 (d, 2H), 6.93 (d, 2H), 5.09 (m, 1H), 4.65-4.55 (m, 1H),4.45-4.25 (m, 1H), 4.18-4.15 (m, 1H), 3.88-3.79 (m, 1H), 1.81 (s, 3H).

Example 95-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carboxylicacid

Step 1 tert-butyl 3-[(4-bromophenoxy)methyl]azetidine-1-carboxylate

A mixture of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (200mg, 1.07 mmol), 4-bromophenol (222 mg, 1.28 mmol), triphenylphosphine(368 mg, 1.40 mmol) and DIAD (259 mg, 1.28 mmol) in anhydrous THF (5 mL)was heated to 110° C. under nitrogen for 5 hours. The reaction mixturewas concentrate in vacuo to give a brown residue, which was purified byflash chromatography (petroleum ether/ethyl acetate 20:1 to 5:1) to givetert-butyl 3-[(4-bromophenoxy)methyl]azetidine-1-carboxylate (310 mg,84%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, 2H), 6.78 (d,2H), 4.06 (m, 4H), 3.79 (m, 2H), 2.96 (m, 1H), 1.45 (s, 9H).

Step 2 3-[(4-bromophenoxy)methyl]azetidine

To a solution of tert-butyl3-[(4-bromophenoxy)methyl]azetidine-1-carboxylate (310 mg, 0.91 mmol) inCH₂Cl₂ (5 mL) was added TFA (5 mL). The reaction mixture was stirred atroom temperature for 16 hours. The reaction mixture was concentrated invacuo to give 3-[(4-bromophenoxy)methyl]azetidine (220 mg, 100%) as ayellow oil which was used directly in the next step.

Step 3 1-{3-[(4-bromophenoxy)methyl]azetidin-1-yl}ethanone

To a solution of 3-[(4-bromophenoxy)methyl]azetidine (220 mg, 0.91 mmol)in CH₂Cl₂ (10 mL) was added triethylamine (276 mg, 2.73 mmol) and aceticanhydride (186 mg, 1.82 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuo togive a yellow oil. The crude product was diluted with ethyl acetate (20ml), washed with 1 N HCl followed by saturated aqueous sodiumbicarbonate solution, dried over sodium sulfate, and concentrated togive 1-{3-[(4-bromophenoxy)methyl]azetidin-1-yl}ethanone (233 mg, 100%)as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, 2H), 6.78 (d,2H), 4.28 (m, 1H), 4.24-4.00 (m, 4H), 3.87 (m, 1H), 3.07 (m, 1H), 1.90(s, 3H)

Step 41-(3-{[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]methyl}azetidin-1-yl)ethanone

To a mixture of 1-{3-[(4-bromophenoxy)methyl]azetidin-1-yl}ethanone (230mg, 0.81 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (201mg, 0.89 mmol) and potassium acetate (397.3 mg, 4.05 mmol) in1,4-dioxane (5 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (59.2 mg,0.081 mmol). The mixture was degassed with nitrogen for 5 minutes. Themixture was heated to 110° C. and stirred under microwave irradiationfor 2 hours. The cooled reaction mixture was filtered and the filtratewas concentrated in vacuo to give a brown residue. The residue waspurified by flash column chromatography (petroleum ether/ethylacetate=20:1 to 3:1) to give1-(3-{[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]methyl}azetidin-1-yl)ethanone(161 mg, 80%) as a brown solid.

Step 55-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carbaldehyde

To a mixture of1-(3-{[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]methyl}azetidin-1-yl)ethanone(160 mg, 0.64 mmol), 5-bromo-6-chloro-1H-indole-3-carbaldehyde (165.4mg, 0.64 mmol) in 2 M aqueous potassium carbonate (1.3 mL, 2M), toluene(3 mL) and ethanol (1 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46 mg,0.064 mmol). The mixture was degassed with nitrogen for 5 minutes. Themixture was heated to 110° C. and stirred under microwave irradiationfor 2 hours. The cooled reaction mixture was extracted with ethylacetate (10 mL×3). The combined organic layers was dried over sodiumsulfate, filtered, and concentrated in vacuo to give a brown residue.The residue was purified by flash column chromatography (petroleumether/ethyl acetate=20:1 to 3:1) to give5-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carbaldehyde(127 mg, 52%) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 10.01 (s, 1H),7.60-7.39 (m, 5H), 6.99 (d, 2H), 4.30 (m, 1H), 4.20-4.09 (m, 4H), 3.93(m, 1H), 3.07 (m, 1H), 1.91 (s, 3H).

Step 65-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carboxylicacid

To a mixture of5-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carbaldehyde(120 mg, 0.31 mmol) in acetonitrile (6 mL) and tert-butanol (6 mL) wasadded 2-methyl-2-butene (2.17 g, 31 mmol). The mixture was cooled to 0°C., and treated with a solution of sodium chlorite (418 mg, 6.2 mmol)and sodium phosphate monobasic hydrate (856 mg, 6.2 mmol) in water (6mL). The reaction mixture was stirred at room temperature for 16 hours.A solution of sodium sulfite was added slowly to the reaction mixture,and stirred for 1 hour. The reaction mixture was partially evaporated invacuo. The aqueous residue was extracted with ethyl acetate (10 mL×3).The combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo to give a brown residue. The residue waspurified by preparative HPLC to give5-{4-[(1-acetylazetidin-3-yl)methoxy]phenyl}-6-chloro-1H-indole-3-carboxylicacid (15 mg, 12%) as a white solid. MS (ES+) 399.0 (M+H)⁺. ¹H NMR (400MHz, CD₃OD): δ 8.01 (m, 2H), 7.57 (s, 1H), 7.39 (d, 2H), 7.03 (d, 2H),4.40 (m, 1H), 4.21 (m, 2H), 4.15 (m, 2H), 3.90 (m, 1H), 3.11 (m, 1H),1.90 (s, 3H).

Example 105-{4-[2-(acetylamino)ethoxy]phenyl}-6-chloro-1H-indole-3-carboxylicacid

Step 1 N-[2-(4-bromophenoxy)ethyl]acetamide

To a solution of 2-(4-bromophenoxy)ethanamine (500 mg, 2.3 mmol) inCH₂Cl₂ (20 mL) was added triethylamine (700 mg, 6.9 mmol) and aceticanhydride (470 mg, 4.6 mmol). The reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was concentrated in vacuoto give a yellow residue. The crude product was diluted with ethylacetate (20 mL), washed with 1 N HCl followed by saturated sodiumbicarbonate, dried over sodium sulfate and concentrated in vacuo to giveN-[2-(4-bromophenoxy)ethyl]acetamide (400 mg, 67%) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 7.39 (d, 2H), 6.76 (d, 2H), δ 5.89 (m, 1H), 4.00(m, 2H), 3.67 (m, 2H), δ 2.01 (s, 3H).

Step 2N-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethyl}acetamide

To a mixture of N-[2-(4-bromophenoxy)ethyl]acetamide (200 mg, 0.78 mmol)in 1,4-dioxane (5 mL) were added5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (193 mg, 0.85 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg,0.077 mmol) and KOAc (380 mg, 3.88 mmol). The mixture was degassed withnitrogen for 3 min and heated to 110° C. by microwave irradiation for 1h. The cooled reaction mixture was concentrated in vacuo to give aresidue, which was dissolved with ethyl acetate (30 mL) and washed withbrine (2×15 mL). The organic layer was dried over sodium sulfate andconcentrated in vacuo to give a residue, which was purified by flashchromatography (petroleum ether/ethyl acetate=10:1 to 4:1) to giveN-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethyl}acetamide(100 mg, 44%) as a yellow solid.

Step 3 N-{2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]ethyl}acetamide

To a solution ofN-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethyl}acetamide(100 mg, 0.35 mmol) in ethanol (1.4 mL) were added5-bromo-6-chloro-1H-indole-3-carbaldehyde (107 mg, 0.42 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg,0.036 mmol), 2 M aqueous potassium carbonate (2 mol/L, 0.7 mL) andtoluene (4.2 mL). The mixture was degassed with nitrogen for 3 min andheated to 110° C. by microwave irradiation for 1 h. The mixture wasconcentrated in vacuo to give a residue, which was dissolved with ethylacetate (50 mL) and washed with brine (2×15 mL). The organic layer wasdried over sodium sulfate and concentrated in vacuo to give a brownresidue, which was purified by flash chromatography (petroleumether/ethyl acetate=10:1 to 2:1) to giveN-{2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]ethyl}acetamide (80 mg,65%) as a yellow solid.

Step 45-{4-[2-(acetylamino)ethoxy]phenyl}-6-chloro-1H-indole-3-carboxylic acid

To a solution ofN-{2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]ethyl}acetamide (80 mg,0.23 mmol) in acetonitrile (3 mL) was added tert-butanol (3 mL) and2-methyl-2-butene (1.89 mL). The reaction mixture was cooled to 0° C.,and treated with a solution of sodium chlorite (452 mg, 6.74 mmol) andsodium phosphate monobasic (930 g, 6.74 mmol) in water (3 mL) dropwise.The reaction mixture was stirred at room temperature for 40 h. Thereaction mixture was quenched with sodium sulfite and concentrated invacuo to give a solid. The crude product was washed with DMF and thefiltrate was concentrated in vacuo to give a brown residue, which waspurified by prep-HPLC to give5-{4-[2-(acetylamino)ethoxy]phenyl}-6-chloro-1H-indole-3-carboxylic acid(22 mg, 26%) as an off-white solid. MS (ES+) 373.1 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 11.93 (s, 1H), 8.14 (br. s., 1H), 8.06 (s, 1H), 7.93 (s,1H), 7.62 (s, 1H), 7.34 (d, 2H), 7.02 (d, 2H), 4.03 (t, 2H), 3.45-3.43(m, 2H), 1.84 (s, 3H).

Example 115-{4-[2-(azetidin-1-yl)-2-oxoethyl]phenyl}-6-chloro-1H-indole-3-carboxylicacid

Step 1 1-(azetidin-1-yl)-2-(4-bromophenyl)ethanone

A mixture of (4-bromophenyl)acetic acid (1 g, 4.65 mmol), azetidinehydrochloride (481 mg, 5.12 mmol), HATU (1.95 g, 5.12 mmol) and NMM(1.03 g, 10.23 mmol) in DMF (30 mL) was stirred at room temperature for16 hours. The reaction mixture was diluted with EtOAc and washed with 1N HCl (15 mL×2) and 1 M aqueous K₂CO₃ (15 mL×2). The organic phase waswashed with brine, dried over sodium sulfate and concentrated in vacuoto give 1-(azetidin-1-yl)-2-(4-bromophenyl)ethanone (1.37 g) as a solidwhich was used directly in the next step without purification. ¹H NMR(400 MHz, CD₃OD) δ 7.47 (d, 2H), 7.197 (d, 2H), 4.26 (t, 2H), 4.01 (t,2H), δ 3.45 (s, 2H), δ 2.30 (p, 2H).

Step 21-(azetidin-1-yl)-2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]ethanone

To a degassed mixture of 1-(azetidin-1-yl)-2-(4-bromophenyl)ethanone(1.37 g, 5.4 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane)(1.83 g, 8.1 mmol) and KOAc (1.59 g, 16.2 mmol) in dry 1,4-dioxane (50mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (198 mg,0.27 mmol). The reaction mixture was heated to reflux for 50 min withstirring. The reaction mixture was acidified with 1 N HCl and extractedwith EtOAc (2×50 mL). The combined organic phases were washed withbrine, dried over sodium sulfate and concentrated to give crude1-(azetidin-1-yl)-2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]ethanone(1.55 g, 100%) which was used directly in the next step.

MS (ES+) 220.0 (M+H)⁺[M=RB(OH)₂].

Step 35-{4-[2-(azetidin-1-yl)-2-oxoethyl]phenyl}-6-chloro-1H-indole-3-carbaldehyde

To a degassed mixture of1-(azetidin-1-yl)-2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]ethanone(0.78 g, 2.7 mmol), 5-bromo-6-chloro-1H-indole-3-carbaldehyde (700 mg,2.7 mmol) and 2 M aqueous K₂CO₃ (5.4 mL, 10.8 mmol) in a solvent mixtureof toluene and EtOH (v/v=3/1, 14 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (197.6 mg,0.27 mmol). The reaction mixture was stirred under microwave irradiationat 120° C. for 30 min. After cooling to room temperature, the reactionmixture was partitioned between water and EtOAc (50 mL/50 mL). Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by flash column (firstEtOAc in Petroleum 25%, then MeOH in DCM 10%) to give5-{4-[2-(azetidin-1-yl)-2-oxoethyl]phenyl}-6-chloro-1H-indole-3-carbaldehyde(0.4 g, 42%) as a brown solid.

MS (ES+) 353.0 (M+H)⁺.

Step 45-{4-[2-(azetidin-1-yl)-2-oxoethyl]phenyl}-6-chloro-1H-indole-3-carboxylicacid

To a solution of5-{4-[2-(azetidin-1-yl)-2-oxoethyl]phenyl}-6-chloro-1H-indole-3-carbaldehyde(0.16 g, 0.453 mmol) in acetonitrile (8 mL) and tert-butanol (8 mL) wasadded 2-methyl-2-butene (8 mL). The reaction mixture was cooled to 0° C.and treated with a solution of sodium chlorite (456 mg, 5 mmol) andsodium phosphate monobasic dihydrate (1.06 g, 6.8 mmol) in water (6 mL).The reaction mixture was stirred for 2 hours at room temperature, andtreated with additional sodium chlorite (607 mg, 6.67 mmol), sodiumphosphate monobasic dihydrate (1.41 g, 9.04 mmol) and 2-methyl-2-butene(1 mL). The resulting mixture was stirred at room temperature overnight.The reaction mixture was partially evaporated in vacuo and extractedwith EtOAc (30 mL×3). The combined organic layers were dried over sodiumsulfate and concentrated in vacuo. The residue was purified viaprep-HPLC to give5-{4-[2-(azetidin-1-yl)-2-oxoethyl]phenyl}-6-chloro-1H-indole-3-carboxylicacid (25 mg) as a yellow solid.

MS (ES+) 369.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (br, 1H), 8.07(s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 7.37-7.32 (m, 4H), 4.21 (m, 2H),3.86 (m, 2H), 3.16 (s, 2H), 2.20 (m, 2H).

Example 126-cyano-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid

Step 1 5-bromo-2,3-dihydro-1H-indole-6-carbonitrile

A solution of 2,3-dihydro-1H-indole-6-carbonitrile (2.5 g, 17.34 mmol)in MeCN (69 mL) was cooled to 0° C. and treated with NBS (3310 mg, 17.7mmol). The light red reaction mixture was stirred at room temperaturefor 20 minutes, and was then poured into saturated aqueous sodiumbicarbonate (200 mL). The product was extracted with ethyl acetate(2×200 mL), and the combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo. The crude product waspurified using flash chromatography eluting with heptanes/ethyl acetate(95:5 to 60:40) to give the title compound (2.26 g, 58%) as a whitesolid. MS (ES−): 219.0, 221.0 (⁷⁹Br M+H, ⁸¹Br M+H).

¹H NMR (400 MHz, CDCl₃) δ 7.32 (s, 1H), 6.78 (s, 1H), 3.65 (t, J=8.6 Hz,2H), 3.09 (t, J=8.6 Hz, 2H).

Step 2 5-bromo-1H-indole-6-carbonitrile

A solution of 2,3-dihydro-1H-indole-6-carbonitrile (1.38 g, 6.18 mmol)in chloroform (61.9 mL) was treated with activated manganese dioxide(2.39 g, 25 mmol) and heated to 60° C. under reflux. After 2 hours, thecooled reaction mixture was filtered through celite, washing withdichloromethane and evaporated in vacuo to give the title compound (1.22g, 89%) as an off-white solid. MS (ES−) 219.0 (M−H)⁻. ¹H NMR (500 MHz,CDCl₃) δ 8.55 (br. s., 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.45 (s, 1H),6.60 (s, 1H).

Step 3 5-bromo-3-formyl-1H-indole-6-carbonitrile

Phosphorus oxychloride (1.39 mL, 14.9 mmol) was added dropwise over 5minutes to DMF (10 mL) with stirring. The clear mixture was stirred atroom temperature for 10 minutes. A solution of5-bromo-1H-indole-6-carbonitrile (1.10 g, 4.97 mmol) in DMF (1.5 with0.5 mL wash) was added to the clear red solution, and the reactionmixture was stirred at room temperature for 5 min. The resulting greysuspension was heated to 80° C. under nitrogen for 25 min, and thenallowed to cool to room temperature. The reaction mixture was treatedslowly with water (30 mL) and aqueous 1 N NaOH (30 mL) at roomtemperature. The resulting thick suspension was then heated to 85° C.for five minutes with vigorous stirring. The reaction mixture wasallowed to cool to room temperature over 5 minutes, and the solids werecollected by filtration. The solids were dried in vacuo for 16 hours at55° C. to afford the title compound (1.15 g, 92%) as a cream-coloredsolid. MS (ES−) 247.1 (M−H)⁻. ¹H NMR (500 MHz, DMSO-d₆) δ 12.76 (br. s.,1H), 9.99 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H).

Step 43-formyl-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-6-carbonitrile

A suspension of 5-bromo-3-formyl-1H-indole-6-carbonitrile (250 mg, 1.00mmol), 1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol(300 mg, 1.16 mmol) and 2 M aqueous potassium carbonate solution (1.26mL, 2.51 mmol) in toluene (2.1 mL) and ethanol (1.25 mL) was degassedwith nitrogen for 10 minutes, then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73.2 mg,0.1 mmol) and heated to 85° C. for 1 hour, at which point the reactionmixture was treated with a solution of1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclobutanol (40 mg)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30 mg)in DMF (0.6 mL). After 3.5 hours, the clear red reaction mixture wascooled to room temperature and poured into half-diluted ammoniumchloride solution (100 mL). The product was extracted with ethyl acetate(6×70 mL). The combined organic layers were dried over sodium sulfate,filtered and evaporated. The crude product was purified using flashchromatograph eluting with heptanes/ethyl acetate (with 0.2% formicacid) (9:1 to 1:9) to give the title compound (223 mg, 70%) as anoff-white solid. MS (ES−) 315.2 (M−H)⁻. ¹H NMR (500 MHz, DMSO-d₆) δ12.62 (br. s., 1H), 10.02 (s, 1H), 8.59 (s, 1H), 8.21 (s, 1H), 8.13 (s,1H), 7.64 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.3 Hz, 2H), 5.59 (s, 1H),2.48-2.43 (m, 2H), 2.32-2.25 (m, 2H), 2.01-1.92 (m, 1H), 1.77-1.67 (m,1H).

Step 5 6-cyano-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylicacid

A solution of3-formyl-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-6-carbonitrile (223mg, 0.705 mmol) in tetrahydrofuran (6 mL) and tert-butanol (6 mL) wastreated with 2-methyl-2-butene (2.25 mL, 21.2 mmol) and cooled to 0° C.The reaction mixture was then treated with a solution of sodium chlorite(594 mg, 7.0 mmol) and sodium phosphate monobasic hydrate (1.0 g, 7.2mmol) and warmed to room temperature. The reaction mixture was stirredvigorously at room temperature for 7 hours, and was then poured intosaturated aqueous ammonium chloride (40 mL). The product was extractedwith ethyl acetate (4×25 mL), and the combined organic layers were driedover sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified using flash chromatography eluting withheptanes/ethyl acetate (with 0.2% formic acid) (85:15 to 0:100). Thefractions containing product were combined, concentrated in vacuo,diluted with toluene (40 mL) and concentrated in vacuo to give the titlecompound (157 mg, 67%) as a white solid. This material was dissolved inethanol (3.5 mL) with heating at 80° C., and treated with water (ca. 3mL) dropwise with heating at 80° C. The resulting solution was stored atroom temperature for two hours, then at 8° C. for 2 hours. The resultingcrystals were collected by filtration, washed with water (2 mL) anddried in vacuo at 60° C. for 14 hours to give the title compound (100mg, 42.7%) as an off-white crystalline solid.

MS (ES−) 331.2 (M−H)⁻. ¹H NMR (500 MHz, DMSO-d₆) δ 12.36 (br. s, 1H),12.34 (br. s, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.63 (d,2H), 7.54 (d, 2H), 5.58 (d, J=1.2 Hz, 1H), 2.48-2.43 (m, 2H), 2.32-2.30(m, 2H), 1.99-1.94 (m, 1H), 1.76-1.66 (m, 1H).

Example 136-chloro-5-[2-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylicacid

Step 1 1-(4-bromo-3-fluorophenyl)cyclobutanol

To 1-bromo-2-fluoro-4-iodobenzene (2390 mg, 7.90 mmol) intetrahydrofuran (20 mL) at −40° C. was added isopropyl magnesiumchloride.lithium chloride (1.3 M in THF, 6.4 mL, 5.1 mmol) dropwise. Thereaction mixture was stirred at −40° C. for 10 minutes, and treated withadditional isopropyl magnesium chloride.lithium chloride (1.3 M in THF,1 mL, 1.3 mmol). The reaction mixture was stirred at −40° C. for anadditional 20 minutes and then treated with cyclobutanone (624 mg, 8.72mmol) dropwise at −40° C. The reaction mixture was warmed to roomtemperature, and stirred at room temperature for 16 hours. The reactionmixture was quenched with water and extracted with ethyl acetate (3×240mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuo to afford the title compound (1.7 g,91%) as an oil.

Step 21-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-fluorophenyl]cyclobutanol

A suspension of 1-(4-bromo-3-fluorophenyl)cyclobutanol (805 mg, 2.6mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (1170 mg, 3.42mmol), potassium acetate (772 mg, 7.88 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (107 mg,0.13 mmol) in 1,4-dioxane (3 mL) was sealed in a reaction vessel andheated to 130° C. for 1 hour. The reaction mixture was diluted withwater (10 mL) and extracted with ethyl acetate (3×10 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedin vacuo. The crude product was purified using flash chromatographyeluting with heptanes/ethyl acetate (0:100 to 50:50) to give the titlecompound (450 mg, 62%).

Step 36-chloro-5-[2-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carbaldehyde

A suspension of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (150 mg, 0.44mmol),1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-fluorophenyl]cyclobutanol(181 mg, 0.652 mmol), 2 M aqueous potassium carbonate (0.87 mL, 1.74mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(18 mg, 0.022 mmol) in ethanol (4 mL) was sealed in a reaction vesseland heated thermally to 130° C. for 3 hours. The reaction mixture wasdiluted with water (10 mL) and extracted with ethyl acetate (3×10 mL).The combined organic layers were washed with brine and dried over sodiumsulfate, filtered and concentrated in vacuo. The crude product waspurified using flash chromatography eluting with heptanes/ethyl acetate(0:100 to 60:40) to give the title compound (57 mg, 58%). ¹H NMR (500MHz, DMSO-d₆) δ 12.18-12.38 (m, 1H), 9.95 (s, 1H), 8.40 (s, 1H), 8.04(s, 1H), 7.73 (s, 1H), 7.34-7.50 (m, 3H), 5.68 (s, 1H), 2.40-2.47 (m,2H), 2.21-2.38 (m, 2H), 1.90-1.99 (m, 1H), 1.68-1.81 (m, 1H).

Step 46-chloro-5-[2-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylicacid

To a solution of6-chloro-5-[2-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carbaldehyde(57 mg, 0.17 mmol) in acetonitrile (1 mL) and tert-butanol (1 mL) wasadded a solution of sodium chlorite (112 mg, 1.7 mmol), sodium phosphatemonobasic hydrate (199 mg, 1.7 mmol) in water (2 mL) and2-methyl-2-butene (0.72 mL, 6.8 mmol). The mixture was stirred at roomtemperature for 24 hours. The mixture was concentrated in vacuo andtreated with ethanol. The solids were filtered and the filtrate wasconcentrated in vacuo to give crude product, which was purified usingreverse phase chromatography to give the title compound (12 mg, 20%). MS(ES+) 360.057 (M+H)⁺. Retention time: 2.60 min. Column: Waters AtlantisdC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95% H₂O/5% MeCNlinear to 5% H₂O/95% MeCN over 4.0 min, HOLD at 5% H₂O/95% MeCN to 5.0min. Flow: 2.0 mL/min.

Example 146-chloro-5-{4-[1-(methoxycarbonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylicacid

Step 1 methyl 3-(4-bromophenyl)pyrrolidine-1-carboxylate

Triethylamine (192 mg, 1.9 mmol) was added to a suspension of3-(4-bromophenyl)pyrrolidine hydrochloride (200 mg, 0.76 mmol) inanhydrous THF (5 mL). The reaction mixture was stirred for 5 minutes andtreated with methyl chloroformate (0.1 g, 1.05 mmol). The reactionmixture was stirred for 16 hours at room temperature. The reactionmixture was diluted with water and extracted with EtOAc (2×15 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give methyl3-(4-bromophenyl)pyrrolidine-1-carboxylate (0.24 g, quantitative yield)as an oil which was used for next step directly. MS (ES+) 283.9 (M+H)⁺.

Step 2 methyl3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]pyrrolidine-1-carboxylate

To a degassed mixture of methyl3-(4-bromophenyl)pyrrolidine-1-carboxylate (0.76 mmol),5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (258 mg, 1.14 mmol)and KOAc (223 mg, 2.28 mmol) in dry 1,4-dioxane (10 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28 mg,0.038 mmol). The resulting mixture was heated to reflux under nitrogenfor 40 min. The reaction mixture was partitioned between water andEtOAc. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash column elutingwith EtOAc/petroleum ether (0:100 to 30:70) to give methyl3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]pyrrolidine-1-carboxylate(158 mg) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.69 (d, J=7.6 Hz,2H), 7.15 (d, J=7.6 Hz, 2H), 3.85-3.81 (m, 1H), 3.69 (s, 4H), 3.65 (s,3H), 3.54-3.50 (m, 1H), 3.43-3.24 (m, 3H), 2.22-2.21 (m, 1H), 1.98-1.89(m, 1H), 0.95 (s, 6H).

Step 3 methyl3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate

To a degassed mixture of methyl3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]pyrrolidine-1-carboxylate(0.158 g, 0.5 mmol), 5-bromo-6-chloro-1H-indole-3-carbaldehyde (142.5mg, 0.55 mmol) and 2 N aqueous potassium carbonate (1.0 mL, 2.0 mmol) intoluene (3 mL) and EtOH (1 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.6 mg,0.05 mmol). The resulting mixture was heated to 115° C. in a microwavefor 30 min. The reaction mixture was partitioned between water andEtOAc. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with EtOAc/petroleum ether (0:100 to 57:43) togive methyl3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate(0.13 g, 68%) as a yellow solid, which was used in the next step withoutfurther purification.

MS (ES+) 383.1 (M+H)⁺.

Step 46-chloro-5-{4-[1-(methoxycarbonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylicacid

To a solution of methyl3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate(124 mg, 0.325 mmol) in acetonitrile (4 mL) and tert-butanol (4 mL) wasadded 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C.and treated with a solution of sodium chlorite (327 mg, 3.59 mmol) andsodium phosphate monobasic dihydrate (761 mg, 4.875 mmol) in water (2mL). After the resulting mixture was stirred for 2 hours at roomtemperature, additional sodium chlorite (435.5 mg, 4.79 mmol) and sodiumphosphate monobasic dihydrate (1.014 g, 6.5 mmol) in water (2 mL) and2-methyl-2-butene (1 mL) was added. The resulting mixture was stirred atroom temperature for 16 h. The reaction mixture was evaporated in vacuoand the aqueous residue was extracted with EtOAc (3×20 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was dissolved in DMSO and purified via prep-HPLC to give6-chloro-5-{4-[1-(methoxycarbonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylicacid (60 mg, 46%) as a white solid. The racemic mixture was separated bypreparative chiral SFC to give 16 mg of peak 1 or Example 14A (>99% ee,ret time=4.73 minutes), and 17 mg of peak 2 or Example 14B (>93% ee, rettime=5.33 minutes) using ChiralPak AD-H Minigram-1, 60/40 CO₂/MeOH 0.2%isopropylamine, 10 mL/min, 120 Bar. MS (ES+) 398.9 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 12.14 (br, 1H), 11.97 (s, 1H), 8.08 (d, 1H), 7.94 (s,1H), 7.61 (s, 1H), 7.38 (m, 4H), 3.81 (m, 1H), 3.61 (s, 3H), 3.54 (m,1H), 3.40 (m, 2H), 3.28 (m, 1H), 2.25 (m, 1H), 2.00 (m, 1H).

Example 155-[4-(1-acetylpyrrolidin-3-yl)phenyl]-6-chloro-1H-indole-3-carboxylicacid

Step 1 1-[3-(4-bromophenyl)pyrrolidin-1-yl]ethanone

Triethylamine (192 mg, 1.9 mmol) was added to a suspension of3-(4-bromophenyl)pyrrolidine hydrochloride (200 mg, 0.76 mmol) inanhydrous THF (5 mL). The mixture was stirred at room temperature for 5minutes and then treated with acetyl chloride (66 mg, 0.84 mmol). Thereaction mixture was stirred for 20 hours at room temperature. Thereaction mixture was diluted with water and extracted with EtOAc (2×20mL). The combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated in vacuo to give1-[3-(4-bromophenyl)pyrrolidin-1-yl]ethanone (0.24 g, quantitativeyield) as an oil which was used directly in the next step. MS (ES+)267.9 (M+H)⁺.

Step 21-{3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]pyrrolidin-1-yl}ethanone

To a degassed mixture of 1-[3-(4-bromophenyl)pyrrolidin-1-yl]ethanone(194 mg, 0.72 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane)(129 mg, 0.57 mmol) and KOAc (212 mg, 2.16 mmol) in dry 1,4-dioxane (8mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26.4 mg,0.036 mmol). The reaction mixture was heated to reflux under nitrogenfor 30 min. After cooling to room temperature, the reaction mixture waspartitioned between water and EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo to give crude1-{3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]pyrrolidin-1-yl}ethanone(340 mg) as an oil which was used in the next step without furtherpurification. MS (ES+) 234.2 (M+H)⁺[M=RB(OH)₂]

Step 35-[4-(1-acetylpyrrolidin-3-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde

To a degassed mixture of crude1-{3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]pyrrolidin-1-yl}ethanone(assume 0.38 mmol), 5-bromo-6-chloro-1H-indole-3-carbaldehyde (98.4 mg,0.38 mmol) and 2 N aqueous potassium carbonate (0.76 mL, 1.52 mmol) intoluene (2.25 mL) and ethanol (0.75 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.8 mg,0.038 mmol). The reaction mixture was heated to 110° C. in a microwavefor 30 minutes. After cooling to room temperature, the reaction mixturewas partitioned between water and EtOAc. The organic phase was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column (first EtOAc in Petroleum ether, then MeOH inCH₂Cl₂) to give5-[4-(1-acetylpyrrolidin-3-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde(52 mg) as an orange solid. MS (ES+) 389.0 (M+Na)⁺

Step 45-[4-(1-acetylpyrrolidin-3-yl)phenyl]-6-chloro-1H-indole-3-carboxylicacid

To a solution of5-[4-(1-acetylpyrrolidin-3-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde(60 mg, 0.163 mmol) in acetonitrile (3 mL) and tert-butanol (3 mL) wasadded 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C.and treated with a solution of sodium chlorite (164 mg, 1.8 mmol) andsodium phosphate monobasic dihydrate (381 mg, 2.445 mmol) in water (1.5mL). The reaction mixture was stirred for 2 hours at room temperatureand treated with additional sodium chlorite (218 mg, 2.4 mmol) andsodium phosphate monobasic dihydrate (509 g, 3.26 mmol) in water (1.5mL) and 2-methyl-2-butene (0.5 mL). The resulting mixture was stirred atroom temperature for an additional 16 h. The reaction mixture wasevaporated in vacuo and the aqueous residue was extracted with EtOAc(3×20 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The residue was dissolved in DMSO and purifiedvia prep-HPLC to give5-[4-(1-acetylpyrrolidin-3-yl)phenyl]-6-chloro-1H-indole-3-carboxylicacid (25 mg) as a white solid. MS (ES+) 383.0 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 11.96 (br, 1H), 8.08 (d, 1H), 7.93 (s, 1H), 7.64 (s, 1H),7.38 (m, 4H), 3.1-3.9 (m, 5H), 2.2-2.5 (m, 1H), 1.9-2.1 (m, 4H).

Example 166-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylicacid

Step 1 3-(4-bromophenyl)-1-(methylsulfonyl)pyrrolidine

Triethylamine (192 mg, 1.9 mmol) was added to a suspension of3-(4-bromophenyl)pyrrolidine hydrochloride (200 mg, 0.76 mmol) inanhydrous THF (5 mL). The reaction mixture was stirred at roomtemperature for 5 minutes and treated with methanesulfonyl chloride (100mg, 0.84 mmol). After the reaction mixture was stirred at roomtemperature for 20 hours, the mixture was diluted with water andextracted with EtOAc (2×20 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give3-(4-bromophenyl)-1-(methylsulfonyl)pyrrolidine (0.25 g, quantitativeyield) as a solid which was used for next step directly. MS (ES+) 303.9,305.9 (⁷⁹Br M+H, ⁸¹Br M+H)⁺

Step 23-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]-1-(methylsulfonyl)pyrrolidine

To a degassed mixture of 3-(4-bromophenyl)-1-(methylsulfonyl)pyrrolidine(125 mg, 0.38 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane)(128.8 mg, 0.57 mmol) and KOAc (112 mg, 1.14 mmol) in dry dioxane (4 mL)was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(14 mg, 0.019 mmol). The reaction mixture was heated to reflux undernitrogen for 30 min. After cooling to room temperature, the reactionmixture was partitioned between water and EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo to give3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]-1-(methylsulfonyl)pyrrolidine(150 mg) as an oil which was used directly in the next step withoutfurther purification.

MS (ES+) 269.7 (M+H)⁺[M=R(OH)₂]

Step 36-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carbaldehyde

To a degassed mixture of crude3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]-1-(methylsulfonyl)pyrrolidine(assume 0.38 mmol), 5-bromo-6-chloro-1H-indole-3-carbaldehyde (98.4 mg,0.38 mmol) and 2 N aqueous potassium carbonate (0.76 mL, 1.52 mmol) intoluene (2.25 mL) and ethanol (0.75 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.8 mg,0.038 mmol). The reaction mixture was heated to 110° C. in a microwavefor 30 min. After cooling to room temperature, the reaction mixture waspartitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting withEtOAc/petroleum ether (0:100 to 100:0) to give6-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carbaldehyde(100 mg) as a yellow solid. MS (ES+) 402.9 (M+H)⁺

Step 46-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylicacid

To a solution of6-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carbaldehyde(120 mg, 0.298 mmol) in acetonitrile (5 mL) and tert-butanol (5 mL) wasadded 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C.and treated with a solution of sodium chlorite (299.5 mg, 3.29 mmol) andsodium phosphate monobasic dihydrate (697 mg, 4.47 mmol) in water (2 mL)dropwise. After the reaction mixture was stirred for 2 h at roomtemperature, additional sodium chlorite (399.3 mg, 4.39 mmol) and sodiumphosphate monobasic dihydrate (930 mg, 5.96 mmol) in H₂O (2 mL) and2-methyl-2-butene (1 mL) was added. The reaction mixture was stirred atroom temperature for 16 h. The reaction mixture was evaporated in vacuoand the aqueous residue was extracted with EtOAc (3×40 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was dissolved in DMSO and purified via prep-HPLC to give6-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carboxylicacid (56 mg) as a white solid.

MS (ES+) 441.0 (M+Na)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (br. s., 1H),11.96 (br, 1H), 8.08 (d, 1H), 7.94 (s, 1H), 7.63 (s, 1H), 7.41 (m, 4H),3.77 (m, 1H), 3.5 (m, 2H), 3.3 (m, 1H), 3.2 (m, 1H), 2.98 (s, 3H), 2.3(m, 1H), 2.1 (m, 1H).

Example 17 6-chloro-5-[4-(pyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1 tert-butyl 3-(4-bromophenyl)pyrrolidine-1-carboxylate

Triethylamine (192 mg, 1.9 mmol) was added to a suspension of3-(4-bromophenyl)pyrrolidine hydrochloride (200 mg, 0.76 mmol) inanhydrous THF (5 mL). The reaction mixture was stirred at roomtemperature for 5 minutes and treated with di-tert-butyl dicarbonate(183 mg, 0.84 mmol). The resulting mixture was stirred for 20 hours atroom temperature. The reaction mixture was diluted with water andextracted with EtOAc (2×15 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to givetert-butyl 3-(4-bromophenyl)pyrrolidine-1-carboxylate (0.29 g,quantitative yield) as an oil which was used directly in the next step.MS (ES+) 269.9 (M−tBu+H)⁺

Step 2 tert-butyl3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]pyrrolidine-1-carboxylate

To a degassed mixture of tert-butyl3-(4-bromophenyl)pyrrolidine-1-carboxylate (124 mg, 0.38 mmol),5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (129 mg, 0.57 mmol)and KOAc (112 mg, 1.14 mmol) in dry 1,4-dioxane (4 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg,0.019 mmol). The resulting mixture was heated to reflux under nitrogenfor 40 minutes. The reaction mixture was partitioned between water andEtOAc. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with EtOAc/petroleum ether (0:100 to 22:78) togive tert-butyl3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]pyrrolidine-1-carboxylate(80 mg) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, 2H), 7.15 (d, 2H), 3.75 (m, 1H), 3.68(s, 4H), 3.58-3.48 (m, 1H), 3.40-3.18 (m, 3H), 2.22-2.18 (m, 1H),1.98-1.85 (m, 1H), 1.40 (s, 9H), 0.95 (s, 6H).

Step 3 tert-butyl3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate

To a degassed mixture of tert-butyl3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]pyrrolidine-1-carboxylate(85 mg, 0.237 mmol), 5-bromo-6-chloro-1H-indole-3-carbaldehyde (67.3 mg,0.26 mmol) and 2 N aqueous potassium carbonate (0.47 mL, 0.94 mmol) intoluene (1.12 mL) and ethanol (0.38 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.3 mg,0.0237 mmol). The reaction mixture was heated to 120° C. in a microwavefor 30 min. The reaction mixture was partitioned between water andEtOAc. The EtOAc layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by preparativethin-layer chromatography (EtOAc/petroleum ether=1:2) to give tert-butyl3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate(40 mg) as a yellow solid. MS (ES+) 447.0 (M+Na)⁺.

Step 45-{4-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]phenyl}-6-chloro-1H-indole-3-carboxylicacid

To a solution of tert-butyl3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate(43 mg, 0.1 mmol) in acetonitrile (1.2 mL) and tert-butanol (1.2 mL) wasadded 2-methyl-2-butene (1.2 mL). The reaction mixture was cooled to 0°C. and treated with a solution of sodium chlorite (100 mg, 1.1 mmol) andsodium phosphate monobasic dihydrate (234 mg, 1.5 mmol) in water (0.6mL). After the resulting mixture was stirred for 2 h at roomtemperature, additional sodium chlorite (134 mg, 1.47 mmol) and sodiumphosphate monobasic dihydrate (312 mg, 2.0 mmol) in H₂O (0.6 mL) wasadded to the reaction mixture. The resulting mixture was stirred at roomtemperature for 16 h. The reaction mixture was concentrated in vacuo andthe aqueous residue was extracted with EtOAc (3×20 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Theresidue was dissolved in DMSO and purified via pre-HPLC to give5-{4-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]phenyl}-6-chloro-1H-indole-3-carboxylicacid (16 mg, 36%) as a white solid. MS (ES+) 463.1 (M+Na)⁺.

Step 5 6-chloro-5-[4-(pyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylicacid

To a mixture of5-{4-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]phenyl}-6-chloro-1H-indole-3-carboxylicacid (15 mg, 0.0341 mmol) in dichloromethane (2 mL) was added TFA (0.213g, 1.87 mmol) and the resulting mixture was stirred for 45 min at roomtemperature. The reaction mixture was concentrated in vacuo to give6-chloro-5-[4-(pyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylic acid (15mg) as an off-white solid. MS (ES+) 341.0 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 11.99 (br, 1H), 8.92 (br, 1H), 8.09 (d, 1H), 7.94 (s, 1H),7.65 (s, 1H), 7.43 (m, 4H), 3.70 (m, 1H), 3.50 (m, 4H), 3.17 (m, 1H),2.04 (m, 1H).

Example 18 6-chloro-5-[4-(oxetan-3-yloxy)phenyl]-1H-indole-3-carboxylicacid

Step 1 3-(4-bromophenoxy)oxetane

To oxetan-3-ol (112 mg, 1.5 mmol) in THF (5 mL) was added 4-bromophenol(200 mg, 1.16 mmol), polymeric triphenylphosphine (0.5 g, 1.5 mmol) andDIAD (305 mg, 1.5 mmol). The reaction mixture was degassed with nitrogenfor 2 min and stirred at 110° C. for 17 hours. The cooled reactionmixture was filtered and the filtrate was concentrated in vacuo to givea residue, which was dissolved in ethyl acetate (50 mL) and washed with2 M NaOH (3×15 mL) and brine (2×20 mL). The organic layer was dried overNa₂SO₄ and concentrated in vacuo to give a residue, which was purifiedby flash chromatography on silica gel eluting with EtOAc/petroleum ether(1:10) to give 3-(4-bromophenoxy)oxetane (140 mg, 53%) as a colorlesssolid. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, 2H), δ 6.55 (d, 2H), 5.19-5.13(m, 1H), 4.97-4.94 (m, 2H), 4.76-4.73 (m, 2H).

Step 2 5,5-dimethyl-2-[4-(oxetan-3-yloxy)phenyl]-1,3,2-dioxaborinane

To a solution of 3-(4-bromophenoxy)oxetane (266 mg, 1.16 mmol) in1,4-dioxane (5 mL) was added5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (288 mg, 1.27 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (83 mg,0.116 mmol) and KOAc (0.57 g, 5.82 mmol). The reaction mixture wasdegassed with nitrogen for 3 min and heated to 110° C. in a microwavefor 1 h. The mixture was concentrated in vacuo to give a residue, whichwas dissolved with ethyl acetate (30 mL) and washed with brine (2×10mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuoto give a residue, which was purified by flash chromatography on silicagel eluting with EtOAc/petroleum ether (1:10 to 1:2) to give5,5-dimethyl-2-[4-(oxetan-3-yloxy)phenyl]-1,3,2-dioxaborinane (90 mg,30%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, 2H), 6.67(d, 2H), 5.23 (m, 1H), 4.99-4.96 (m, 2H), 4.78-4.75 (m, 2H), 3.75 (s,4H), 1.01 (s, 6H).

Step 3 6-chloro-5-[4-(oxetan-3-yloxy)phenyl]-1H-indole-3-carbaldehyde

To a solution of5,5-dimethyl-2-[4-(oxetan-3-yloxy)phenyl]-1,3,2-dioxaborinane (90 mg,0.35 mmol) in ethanol (1.4 mL) was added5-bromo-6-chloro-1H-indole-3-carbaldehyde (110 mg, 0.43 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg,0.036 mmol), 2 M aqueous potassium carbonate (0.7 mL, 1.4 mmol) andtoluene (4 mL). The mixture was degassed with N₂ for 3 min and heated to110° C. by microwave irradiation for 1 h. The mixture was concentratedin vacuo to give a residue, which was dissolved with ethyl acetate (30mL) and washed with brine (2×10 mL). The organic layer was dried overNa₂SO₄ and concentrated in vacuo to give a residue, which was purifiedby flash chromatography on silica gel eluting with EtOAc/petroleum ether(1:10 to 1:1) to give6-chloro-5-[4-(oxetan-3-yloxy)phenyl]-1H-indole-3-carbaldehyde (100 mg,87%) as a colorless oil.

Step 4 6-chloro-5-[4-(oxetan-3-yloxy)phenyl]-1H-indole-3-carboxylic acid

To a solution of6-chloro-5-[4-(oxetan-3-yloxy)phenyl]-1H-indole-3-carbaldehyde (100 mg,0.34 mmol) in acetonitrile (4 mL) was added tert-butanol (4 mL), water(4 mL) and 2-methyl-2-butene (2.52 mL). The reaction mixture was stirredfor 2 minutes and treated with sodium chlorite (620 mg, 9.25 mmol) andsodium phosphate monobasic (1.45 g, 9.29 mmol). The mixture was stirredat room temperature for 17 hours. The reaction was quenched with sodiumsulfite and the mixture was concentrated in vacuo to give a residue,which was extracted with ethyl acetate (3×10 mL). The combined organiclayers were washed with brine (2×10 mL), dried over Na₂SO₄ andconcentrated in vacuo to give a residue, which was purified by prep-HPLCto give 6-chloro-5-[4-(oxetan-3-yloxy)phenyl]-1H-indole-3-carboxylicacid (45 mg, 42%) as an off-white solid. MS (ES+) 343.9 (M+H)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 11.32 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.62 (s,1H), 7.35 (d, 2H), 6.87 (d, 2H), 5.35-5.32 (m, 1H), 4.97-4.94 (m, 2H),4.61-4.58 (m, 2H).

Example 196-chloro-5-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid

Step 1 4-[2-(4-bromophenoxy)ethyl]morpholine

To a mixture of 2-(morpholin-4-yl)ethanol (197 mg, 1.5 mmol) in THF (5mL) was added 4-bromophenol (200 mg, 1.16 mmol), polymerictriphenylphosphine (0.5 g, 1.5 mmol) and DIAD (305 mg, 1.5 mmol). Themixture was degassed with nitrogen for 2 min and stirred at 110° C. for17 hours. The cooled reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give a residue, which was dissolved with ethylacetate (50 mL), washed with 2 M aqueous NaOH (3×15 mL) and brine (2×20mL). The organic layer was dried over sodium sulfate and concentrated invacuo to give a residue, which was purified by flash chromatography onsilica gel to give 4-[2-(4-bromophenoxy)ethyl]morpholine (480 mg, 100%)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.35 (d, 2H), δ 6.70 (d,2H), 4.07 (t, 2H), 3.74-3.71 (m, 4H), 2.78 (t, 2H), 2.57-2.55 (m, 4H).

Step 24-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethyl}morpholine

To a solution of 4-[2-(4-bromophenoxy)ethyl]morpholine (498 mg, 1.74mmol) in 1,4-dioxane (10 mL) was added5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (431 mg, 1.91 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (124 mg,0.174 mmol) and KOAc (0.853 g, 8.7 mmol). The mixture was degassed withnitrogen for 3 min and heated to 110° C. by microwave irradiation for 1h. The mixture was concentrated in vacuo to give a residue, which wasdissolved with ethyl acetate (50 mL) and washed with brine (2×15 mL).The organic layer was dried over Na₂SO₄ and concentrated in vacuo togive a residue, which was purified by flash chromatography to give4-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethyl}morpholine(190 mg, 34%) as a colorless oil.

Step 36-chloro-5-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-1H-indole-3-carbaldehyde

To a solution of4-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethyl}morpholine(190 mg, 0.6 mmol) in ethanol (2.4 mL) were added5-bromo-6-chloro-1H-indole-3-carbaldehyde (187 mg, 0.72 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (45 mg, 0.06mmol), 2 M aqueous potassium carbonate (1.2 mL, 2.4 mmol) and toluene (7mL). The mixture was degassed with nitrogen for 3 min and heated to 110°C. by microwave irradiation for 1 h. The mixture was concentrated invacuo to give a residue, which was dissolved with ethyl acetate (50 mL)and washed with brine (2×15 mL). The organic layer was dried over Na₂SO₄and concentrated in vacuo to give a residue, which was purified by flashchromatography to give6-chloro-5-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-1H-indole-3-carbaldehyde(130 mg, 57%) as a yellow oil.

Step 46-chloro-5-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid

To a solution of6-chloro-5-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-1H-indole-3-carbaldehyde(130 mg, 0.34 mmol) in acetonitrile (4 mL) was added tert-butanol (4mL), water (4 mL) and 2-methyl-2-butene (2.76 mL). After stirred for 2min, sodium chlorite (680 mg, 10.15 mmol) and sodium phosphate monobasic(1.59 mg, 10.19 mmol) were added to the reaction mixture. The mixturewas stirred at room temperature for 16 hours. The reaction was quenchedwith sodium sulfite and the mixture was concentrated in vacuo to give aresidue, which was extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with brine (2×15 mL), dried over Na₂SO₄ andconcentrated in vacuo to give a residue, which was purified by prep-HPLCto give6-chloro-5-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid (30 mg, 22%) as a yellow solid. MS (ES+) 401.1 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.28 (s, 1H), 8.02 (s, 1H), 7.98 (s, 1H) 7.57 (s, 1H),7.39 (d, 2H), 7.04 (d, 2H), 4.31 (m, 2H), 3.83 (m, 4H), 3.17 (m, 2H),2.96 (m, 4H).

Example 204,6-difluoro-5-[4-(3-hydroxyoxetan-3-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1 4-bromo-3,5-difluoro-2-iodoaniline

To a solution of the 4-bromo-3,5-difluoroaniline (5 g, 20 mmol) inacetic acid (60 mL) was added NIS (5.68 g). The reaction mixture wasstirred at room temperature for two hours, and poured into water (300mL). The product was extracted with ethyl acetate (2×200 mL), and thecombined organic layers were washed with 1 N aqueous NaOH (200 mL) andsaturated aqueous sodium thiosulfate (100 mL). The organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo. The oilyresidue was filtered through a plug of silica gel, eluting withheptane/ethyl acetate (4:1). The filtrate was concentrated in vacuo togive the title compound (7.34 g) as a white solid. ¹H NMR (500 MHz,CDCl₃) δ 6.44 (dd, J=10.00, 1.95 Hz, 1H) 4.46 (br. s., 2H).

Step 2 4-bromo-3,5-difluoro-2-[(trimethylsilyl)ethynyl]aniline

A solution of 4-bromo-3,5-difluoro-2-iodoaniline (3.0 g, 9.0 mmol) intriethylamine (50 mL) was degassed with nitrogen for 10 minutes, thentreated with copper iodide (209 mg, 1.10 mmol),Dichlorobis(triphenylphosphine)palladium(II), (769 mg 1.10 mmol), andethynyl(trimethyl)silane (1.42 mL, 10.1 mmol). The reaction mixture wasstirred at room temperature for 10 minutes. The reaction mixture turneddark and formed a precipitate. After two hours, the reaction mixture wastreated with DMF (8 mL) and stirred for an additional 72 hours at roomtemperature. The reaction mixture was heated to 50° C. for 16 hours.After cooling to room temperature, the reaction mixture was concentratedin vacuo, azeotroping with heptanes (3×100 mL). The black oil waspartitioned between diethyl ether (300 mL) and water (300 mL), and theorganic phase was washed with brine, dried over sodium sulfate, filteredand concentrated in vacuo to give a dark solid. The crude product waspurified by flash chromatography to give the title compound (1.75 g). MS(ES+) 306.0 ((M+2)+H)⁺.

Step 3 5-bromo-4,6-difluoro-1H-indole

A solution of 4-bromo-3,5-difluoro-2-[(trimethylsilyl)ethynyl]aniline(1.75 g, 5.77 mmol) in DMF (80 mL) was treated with copper iodide (2.2g, 11.5 mmol). The reaction mixture was sealed and heated to 110° C. for3.75 hours. The black reaction mixture was cooled to room temperature,and poured into saturated aqueous ammonium chloride (300 mL). Theproduct was extracted with ethyl acetate/heptane (2:1, 3×200 mL), andthe combined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo to give a black oil. The crude product waspurified using flash chromatography on silica gel, eluting withheptanes/EtOAc (100:0 to 1:1) to give the title compound (350 mg). MS(ES+) 233.9 ((M+2)+H)⁺

Step 4 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde

To a solution of 5-bromo-4,6-difluoro-1H-indole (285 mg, 1.23 mmol) inDMF (2 mL) was added N-(chloromethylidene)-N-methylmethanaminium (236mg, 1.84 mmol) at room temperature. The reaction mixture was stirred for30 min, and treated with additionalN-(chloromethylidene)-N-methylmethanaminium (100 mg). The mixture wasstirred for an additional 30 minutes at room temperature. The reactionmixture was then treated with 1 N aqueous NaOH (2.5 mL) and water (2.5mL). The mixture was stirred at 100° C. for 30 min. After cooling toroom temperature, the solvents were evaporated in vacuo, and the residuewas diluted with THF (2 mL) and water (2 mL). The resulting mixture wasstirred at room temperature for 2 hours, and the resulting solids werecollected by filtration. The solids were washed with water and heptanesand dried in vacuo to give the title compound (157 mg) as a brown solid.MS (ES+) 261.8 ((M+2)+H)⁺.

Step 5 3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]oxetan-3-ol

A mixture of 3-(4-bromophenyl)oxetan-3-ol (345 mg, 1.51 mmol),5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (374 mg, 1.66 mmol),KOAc (704 mg, 7.18 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg,0.075 mmol) was sealed in a reaction vessel and evacuated andback-filled with nitrogen. The reaction mixture was diluted withanhydrous deoxygenated 1,4-dioxane (5 mL) and heated to 110° C. for 15hours. The cooled reaction mixture was filtered through celite, elutingwith ethyl acetate. The filtrate was concentrated in vacuo to give thetitle compound.

Step 64,6-difluoro-5-[4-(3-hydroxyoxetan-3-yl)phenyl]-1H-indole-3-carbaldehyde

A mixture of 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (157 mg, 0.64mmol), 3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]oxetan-3-ol(190 mg, 0.725 mmol), and 2 M aqueous potassium carbonate (1.2 mL, 2.4mmol) in toluene (4 mL) and ethanol (2 mL) was degassed with nitrogenfor 10 minutes, then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg, 0.06mmol). The reaction mixture was sealed and heated to for 110° C. for 16hours. The cooled reaction mixture was diluted with ethyl acetate andammonium chloride. The layers were separated and the organic layer waswashed with brine, dried over sodium sulfate, and concentrated in vacuo.The crude product was purified by flash column chromatography to givethe title compound (38 mg).

Step 74,6-difluoro-5-[4-(3-hydroxyoxetan-3-yl)phenyl]-1H-indole-3-carboxylicacid

A solution of4,6-difluoro-5-[4-(3-hydroxyoxetan-3-yl)phenyl]-1H-indole-3-carbaldehyde(38 mg, 0.12 mmol) was dissolved in acetonitrile (1 mL) and warmtert-butanol (0.3 mL). The reaction mixture was treated with2-methyl-2-butene (0.3 ml), cooled to 0° C., and treated with a solutionof sodium chlorite (199 mg, 2.36 mmol) and sodium phosphate monobasichydrate (332 mg, 2.41 mmol) in water (1 mL) via addition funnel. The icebath was removed, and the reaction mixture was warmed to roomtemperature and stirred for 5 hours. The reaction mixture was dilutedwith water (2 mL) and NH₄Cl (2 mL). The product was extracted with EtOAc(3×20 mL). The organic layer was concentrated in vacuo to give the crudeproduct, which was purified using prep-HPLC to give the title compound(4.3 mg). MS (ES+) 346.0 (M+H)⁺. Retention time: 2.04 min. Column:Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95%H₂O/5% MeCN linear to 5% H₂O/95% MeCN over 4.0 min, HOLD at 5% H₂O/95%MeCN to 5.0 min. Flow: 2.0 mL/min.

Example 21 2,2-dimethylpropoxy)phenyl]-1H-indole-3-carboxylic acid

Step 1 3-(4-bromophenoxy)-2,2-dimethylpropan-1-ol

To a mixture of 4-bromophenol (300 mg, 1.74 mmol) in DMF (10 mL) wasadded 3-bromo-2,2-dimethylpropan-1-ol (579 mg, 3.47 mmol) and potassiumcarbonate (720 mg, 5.22 mmol). The mixture was degassed with nitrogenthree times and heated to 90° C. for 48 h. The mixture was cooled toroom temperature and then filtered. The filtrate was concentrated invacuo to give a residue, which was purified by flash chromatography(EtOAc/petroleum ether=1:10 to 1:1) to give3-(4-bromophenoxy)-2,2-dimethylpropan-1-ol (130 mg, 29%) as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, 2H), 6.79 (d, 2H), 3.73 (s, 2H),3.54 (s, 2H), 1.02 (s, 6H).

Step 23-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]-2,2-dimethylpropan-1-ol

To a solution of 3-(4-bromophenoxy)-2,2-dimethylpropan-1-ol (130 mg, 0.5mmol) in 1,4-dioxane (10 mL) was added5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (125 mg, 0.55 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05mmol) and potassium acetate (245 mg, 2.5 mmol). The mixture was degassedwith nitrogen for 3 min and heated to 110° C. by microwave irradiationfor 1 h. The cooled reaction mixture was concentrated in vacuo to give aresidue, which was dissolved with ethyl acetate (30 mL) and washed withbrine (3×10 mL). The organic layer was dried over sodium sulfate andconcentrated in vacuo to give a residue, which was purified by flashchromatography (EtOAc/petroleum ether=1:10 to 1:2) to give3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]-2,2-dimethylpropan-1-ol(60 mg, 41%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, 2H),6.89 (d, 2H), 3.79 (s, 2H), 3.75 (s, 4H), 3.55 (s, 2H), 1.03 (s, 6H),1.01 (s, 6H).

Step 36-chloro-5-[4-(3-hydroxy-2,2-dimethylpropoxy)phenyl]-1H-indole-3-carbaldehyde

To a solution of3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]-2,2-dimethylpropan-1-ol(60 mg, 0.21 mmol) in toluene (6 mL) was added5-bromo-6-chloro-1H-indole-3-carbaldehyde (64 mg, 0.25 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg,0.021 mmol), 2 M aqueous potassium carbonate (0.42 mL, 0.84 mmol) andethanol (2 mL). The reaction mixture was degassed with nitrogen for 3min and heated to 110° C. by microwave irradiation for 1 h. The cooledreaction mixture was concentrated in vacuo to give a residue, which wasdissolved with ethyl acetate (30 mL) and washed with brine (2×10 mL).The organic layer was dried over sodium sulfate and concentrated invacuo to give a residue, which was purified by flash chromatography togive6-chloro-5-[4-(3-hydroxy-2,2-dimethylpropoxy)phenyl]-1H-indole-3-carbaldehyde(60 mg, 82%) as an off-white solid.

Step 4 2,2-dimethylpropoxy)phenyl]-1H-indole-3-carboxylic acid

To a solution of6-chloro-5-[4-(3-hydroxy-2,2-dimethylpropoxy)phenyl]-1H-indole-3-carbaldehyde(60 mg, 0.17 mmol) in acetonitrile (3 mL) was added tert-butanol (3 mL),water (3 mL) and 2-methyl-2-butene (1.38 mL). The reaction mixture wasstirred for 2 min then treated with sodium chlorite (338 mg, 3.76 mmol)and sodium phosphate monobasic (787 mg, 5.04 mmol). The mixture wasstirred at room temperature overnight. The reaction was quenched withsodium sulfite and concentrated in vacuo to give a residue, which wasdissolved with ethyl acetate (50 mL), washed with brine (3×15 mL), driedover sodium sulfate and concentrated in vacuo. The residue was purifiedby prep-HPLC to give 2,2-dimethylpropoxy)phenyl]-1H-indole-3-carboxylicacid (20 mg, 32%) as an off-white solid. MS (ES−) 372.1 (M−H)⁻. ¹H NMR(400 MHz, CD₃OD) δ 8.01 (s, 1H), 7.99 (s, 1H) 7.56 (s, 1H), 7.35 (d,2H), 6.98 (d, 2H), 3.80 (s, 2H), 3.49 (s, 2H), 1.04 (s, 6H).

Example 224,6-difluoro-5-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)-1H-indole-3-carboxylicacid

Step 1{1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclopropyl}methanol

To a solution of [1-(4-bromophenyl)cyclopropyl]methanol (1200 mg, 5.3mmol) in THF (40 mL) was added5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (1600 mg, 6.87 mmol),KOAc (2600 mg, 26.5 mmol) and Pd(dppf)Cl₂ (197 mg, 0.27 mmol) at roomtemperature under N₂. The reaction mixture was stirred at 70° C. underN₂ for 3 hours. The reaction was filtered, the filtrate wasconcentrated, and purified by column chromatography to give the titlecompound (1.3 g, 95%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.74(d, 2H), 7.34 (d, 2H), 3.75 (s, 4H), 3.68 (s, 2H), 0.99 (s, 6H), 0.88(m, 2H), 0.85 (m, 2H).

Step 24,6-difluoro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carbaldehyde

A solution of 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (200 mg,0.77 mmol) and{1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclopropyl}methanol(200 mg, 0.77 mmol) in toluene (6 mL) and EtOH (2 mL) was added asolution of potassium carbonate (318 mg, 2.31 mmol) in water (1.0 mL)and Pd(dppf)Cl₂ (31 mg, 0.04 mmol) at room temperature under N₂. Thereaction was cooled to room temperature, and extracted with ethylacetate (20 mL×3). The organic layers were washed with brine (20 mL),dried over sodium sulfate, concentrated, and purified by columnchromatography to give the title compound (70 mg, 28%) as a yellowsolid. ¹H NMR (400 MHz, CD₃OD) δ 10.00 (s, 1H), 8.12 (s, 1H), 7.49 (d,2H), 7.40 (d, 2H), 7.19 (d, 1H), 3.69 (s, 2H), 0.89 (s, 4H).

Step 34,6-difluoro-5-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)-1H-indole-3-carboxylicacid

To a solution of4,6-difluoro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carbaldehyde(70 mg, 0.214 mmol) in acetonitrile (4.6 mL), t-Butanol (4.6 mL) and2-methyl-2-butene (3.0 mL) was added a solution of sodium chlorite (289mg, 4.28 mmol) and NaH₂PO₄ (590 mg, 4.28 mmol) in water (4.6 mL) at 0°C. The reaction mixture was stirred at room temperature for 18 h. Thereaction was quenched with a solution of sodium sulfate (674 mg, 5.35mmol) in water (5.0 mL), and extracted with ethyl acetate (20 mL×3). Theorganic layers were washed with brine (20 mL×1) and dried over sodiumsulfate, filtered, concentrated, and purified which was purified bypreparative HPLC to give the title compound (17.4 mg, 24%) as a whitesolid. MS (AP+) 343.9 (M+1)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.00 (s, 1H),7.48 (d, 2H), 7.39 (d, 2H), 7.11 (d, 1H), 3.71 (s, 2H), 0.91 (s, 4H).

Example 236-cyano-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carboxylicacid

Step 13-formyl-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-6-carbonitrile

To a suspension of 5-bromo-3-formyl-1H-indole-6-carbonitrile (300 mg,1.20 mmol) and{1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclopropyl}methanol(358 mg, 1.10 mmol) in toluene (4 mL) and ethanol (2 mL) was added 2 Maq. potassium carbonate (2 mL, 4 mmol) then was degassed with nitrogenfor 10 minutes. The reaction was treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium anddichloromethane (98 mg, 0.12 mmol). The reaction mixture was heated to115° C. in a sealed 20 mL microwave vial for 2 hours. The reactionmixture was allowed to cool slowly to room temperature and stirred for16 hours. The reaction was diluted with ethyl acetate (50 mL) and water(50 mL) and filtered through a pad of celite. The filtrate was extractedand the layers were separated. The aqueous layer was washed anadditional time with ethyl acetate. The combined organic layers werewashed with brine, dried over magnesium sulfate, filtered andconcentrated under reduced pressure. The magnesium sulfate was washedwith a 20% methanol/dichloromethane solution and concentrated underreduced pressure yielding 370 mg of crude. Methanol (40 mL) was passedthrough the above pad of celite and the filtrate was concentrated underreduced pressure yielding 100 mg of a yellow solid. The crude materialswere combined and purified using the Biotage SP4 automatedchromatography unit (SNAP 50 g silica gel column) and eluting with agradient of 0-100% ethyl acetate followed by a gradient of 0-20%methanol/dichloromethane to yield 236 mg (62%) of the title compound asa solid. MS (ES+) 315.5 (M−H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.98 (s, 1H),8.38 (s, 1H), 8.30 (d, 1H), 7.99 (d, 1H), 7.52 (d, 4H), 3.71 (s, 2H),0.93 (m, 4H)

Step 26-cyano-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carboxylicacid

A partial solution/suspension of3-formyl-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-6-carbonitrile(236 mg, 0.746 mmol) in tetrahydrofuran/t-butanol (6 mL/6 mL) wastreated with 2-methyl-2-butene (4 mL, 40 mmol) followed by a solution ofsodium chlorite (942 mg, 11 mmol) and sodium phosphate (monobasic andmonohydrate, 1585 mg, 11.48 mmol) in water (4 mL) via glass pipet. Thereaction was stoppered and allowed to stir overnight at roomtemperature. After 16 hours, the reaction mixture was poured intohalf-diluted saturated aqueous ammonium chloride solution (50 mL) andextracted with ethyl acetate (three times). The combined organic layerswere washed with brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure to yield 346 mg of the crude desiredproduct. The crude material was diluted with methanol (25 mL) and themixture was heated to reflux. The resulting solution was allowed to coolto room temperature slowly. As the solution was cooling, the sides ofthe flask were scratched with a glass pipette and stirred at roomtemperature for 4 hours resulting in a precipitate. The precipitateshowed birefringence under the microscope and the mixture was allowed tostir overnight at room temperature (18 hours). After 18 hours, themixture was filtered and the filter cake was washed with methanol (2 mL)and dried under high vacuum for 40 minutes yielding 127 mg (51%) ofdesired product as a crystalline solid. The melting point range wasdetermined by a starting temperature of 250° C. and a gradient of 2°C./minute which produced a melting point of 270.9-271.6° C. (determinedby the Buchi Melting Point B-545). MS (ES+) 331.4 (M−H)⁺. ¹H NMR (400MHz, DMSO-d₆) δppm 12.35 (br. s, 1H), 12.33 (br. s, 1H), 8.29 (d, J=2.3Hz, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.43 (d,J=8.4 Hz, 2H), 4.73 (t, J=5.7 Hz, 1H), 3.60 (d, J=5.7 Hz, 2H), 0.86-0.93(m, 2H), 0.78-0.85 (m, 2H).

Example 244,6-difluoro-5-[4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carboxylic acid

Step 1 2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethanol

A mixture bis(neopentyl glycolato)diboron (8.52 g, 24.96 mmol), ovendried potassium acetate (10.4 g, 105.97 mmol), and2-(4-bromo-phenoxy)-ethanol (4.93 g, 22.71 mmol) in 1,4-dioxane (60 mL)in a 250 mL round bottom flask was degassed with nitrogen for 10 minutesthen treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium, dichloromethane (1.26 g, 1.544 mmol) and heated to 100° C.overnight (16 hours). The following morning, the reaction mixture wasdiluted with ethyl acetate and filtered through a plug of celite washingwith ethyl acetate. The filtrate was concentrated under reducedpressure. The crude material (17.7 g) was divided into two batches andwere purified using the Biotage SP4 automated chromatography unit (SNAP100 g silica gel column for each lot) and eluting with a gradient of0-100% ethyl acetate/heptane yielding 5.28 g (93%) of the title compound(9.7:1 desired product to boronate bi-products). ¹H NMR (400 MHz, CDCl₃)δppm 7.74 (d, 2H), 6.90 (d, 2H), 4.19-4.02 (m, 2H), 4.01-3.85 (m, 2H),3.75 (s, 4H), 1.02 (s, 6H).

Step 24,6-difluoro-5-[4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde

A solution of 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (150 mg,0.58 mmol) and2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethanol (158 mg, 0.64mmol) in toluene (5 mL) and EtOH (1.6 mL) was added to a solution ofpotassium carbonate (240 mg, 1.74 mmol) in water (1.2 mL) andPd(dppf)Cl₂ (24 mg, 0.029 mmol) at room temperature under N₂. TLC(petroleum ether/EtOAc=1:1) showed the reaction was complete. Thereaction was cooled to room temperature, and extracted with ethylacetate (20 mL×2). The organic layers were washed with brine (10 mL),dried over sodium sulfate, concentrated in vacuo, and purified by columnchromatography to give the title compound (70 mg, 38%) as a yellowsolid.

¹H NMR (400 MHz, CD₃OD) δ 10.00 (s, 1H), 8.13 (s, 1H), 7.49 (d, 2H),7.19 (d, 1H), 7.05 (d, 2H), 4.12 (t, 2H), 3.90 (t, 2H).

Step 3 4,6-difluoro-5-[4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carboxylicacid

To a solution of4,6-difluoro-5-[4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde (70mg, 0.221 mmol) in acetonitrile (4.6 mL), t-butanol (4.6 mL) and2-methyl-2-butene (3.0 mL) was added a solution of sodium chlorite (298mg, 4.42 mmol) and sodium dihydrogen phosphate (610 mg, 4.42 mmol) inwater (4.6 mL) in an ice-bath. The reaction mixture was stirred at roomtemperature for 18 h. TLC (petroleum ether/EtOAc=1:1) showed thereaction was complete. The reaction was quenched with a solution ofsodium sulfite (612 mg, 4.86 mmol) in water (5.0 mL), and extracted withethyl acetate (20 mL×3). The organic layers were washed with brine (10mL) and dried over sodium sulfate, filtered and concentrated to give acrude residue, which was purified by reverse phase HPLC to give thetitle compound (21.1 mg, 29%) as a white solid. MS (AP+) 333.9 (M+1)⁺.¹H NMR (400 MHz, CD₃OD) δ 8.00 (s, 1H), 7.49 (d, 2H), 7.12 (d, 1H), 7.05(d, 2H), 4.13 (t, 2H), 3.92 (t, 2H)

Example 256-fluoro-5-[4-(1-hydroxycyclobutyl)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

Step 11-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]cyclobutanol

A 250 mL round bottom flask was charged with1-(4-bromo-2-methoxyphenyl)cyclobutanol (4.756 g, 18.50 mmol), dioxane(90 mL), bis(neopentyl glycolato)diboron (4.60 g, 20.3 mmol), andpotassium acetate (oven dried, 9.08 g, 92.5 mmol). Nitrogen was bubbledthrough the solution for 10 minutes.[1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium,dichloromethane (1.09 g, 1.33 mmol) was then added and the reaction washeated to reflux for 3 hours. The reaction mixture was cooled to roomtemperature and filtered through celite, washed with ethyl acetate, andconcentrated under reduced pressure. The crude material was purifiedusing the Biotage Isolera One (SNAP 100 g silica gel column) and elutedwith a gradient of 0-100% ethyl acetate/heptane yielding 4.86 g (90%) ofthe title compound as an oil that solidified upon standing. GC/MS: 289(m/z). ¹H NMR (500 MHz, CDCl₃) δ 7.42 (d, J=7.3 Hz, 1H), 7.34 (s, 1H),7.31 (d, J=7.6 Hz, 1H), 3.92 (s, 3H), 3.77 (s, 4H), 2.43-2.58 (m, 2H),2.28-2.42 (m, 2H), 1.94-2.10 (m, 1H), 1.58-1.69 (m, 1H), 1.03 (s, 6H)

Step 26-fluoro-5-[4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl]-1H-indole-3-carbaldehyde

To a solution of3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]oxetan-3-ol(101 mg, 0.348 mmol) and 5-bromo-6-fluoro-1H-indole-3-carbaldehyde (88.5mg, 0.365 mmol) in toluene/ethanol (8 mL, 3:1) was added 2 N potassiumcarbonate (145 mg, 1.051 mmol) and Pd(dppf)Cl₂ (30 mg, 0.041 mol). Thereaction was degassed with N₂ for 2 minutes. The reaction was heated to110° C. for 3 hours. The reaction mixture was concentrated to give acrude residue, which was purified by column chromatography on a silicagel to afford the title compound (86 mg, 73%) as an off-white solid. ¹HNMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.80 (br. s, 1H), 8.32 (d, 1H),7.79 (d, 1H), 7.32 (d, 1H), 7.15 (m, 2H), 7.07 (s, 1H), 3.88 (s, 3H),3.62 (s, 1H), 2.50 (m, 2H), 2.34 (m, 2H), 1.98 (m, 1H), 1.64 (m, 1H)

Step 36-fluoro-5-[4-(1-hydroxycyclobutyl)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

6-fluoro-5-[4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl]-1H-indole-3-carbaldehyde(86 mg, 0.2534 mmol) was dissolved in MeCN (6 mL) and warm t-butanol (6mL). 2-methyl-2-butene (4 mL) was then added and cooled to 0° C. Sodiumchlorite (342 mg, 5.07 mmol) and sodium dihydrogen phosphate dihydrate(791 mg, 5.07 mmol) were dissolved in water (3 mL). The aqueous solutionwas added to the organic solution dropwise via addition funnel and theice bath was removed and the mixture was allowed to warm to roomtemperature. The reaction was quenched with saturated aqueous sodiumsulfite, concentrated to remove the organics and extracted with EtOAc(20 mL×3). The combined organics were washed with brine (20 mL), driedand concentrated to give a crude residue, which was purified by prepHPLC to afford the title compound (7.3 mg, 8.1%) as an off-white solid.

MS (AP+) 337.8 (M−H₂O+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 1H),11.90 (s, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.35 (d, 2H), 7.08 (s, 1H),7.04 (d, 1H), 5.00 (s, 1H), 3.82 (s, 3H), 2.60 (m, 2H), 2.20 (m, 2H),2.00 (m, 1H), 1.61 (m, 1H).

Example 264,6-difluoro-5-[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1 2-(4-bromophenyl)-2-methylpropan-1-ol

To a solution of[2-(4-bromophenyl)-2-methylpropoxy](tert-butyl)dimethylsilane (500 mg,1.46 mmol) in MeOH (5 mL) was added dropwise HCl/MeOH (5 mL) at roomtemperature. The reaction mixture was stirred at room temperature for 2hours. The reaction was concentrated to give a crude residue, which waspurified by column chromatography to give the title compound (250 mg,75%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, 2H), 7.19(d, 2H), 3.50 (s, 2H), 1.23 (s, 6H).

Step 22-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]-2-methylpropan-1-ol

To a solution of 2-(4-bromophenyl)-2-methylpropan-1-ol (250 mg, 1.1mmol) and 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (298 mg, 1.3mmol) in THF (20 mL) was added KOAc (539 mg, 5.5 mmol) and Pd(dppf)Cl₂(40 mg, 0.055 mmol) at room temperature under N₂. The reaction wasfiltered and the filtrate was concentrated to give a crude, which waspurified by column chromatography to give the title compound (120 mg,42%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, 2H), 7.32 (d,2H), 3.69 (s, 4H), 3.56 (m, 2H), 1.27 (s, 6H), 0.95 (s, 6H)

Step 34,6-difluoro-5-[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]-1H-indole-3-carbaldehyde

To a solution of2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]-2-methylpropan-1-ol(102 mg, 0.386 mmol) and 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde(100 mg, 0.386 mmol) in toluene (6 mL) and EtOH (2 mL) was added asolution of potassium carbonate (160 mg, 1.159 mmol) in water (1.0 mL)and Pd(dppf)Cl₂ (15.8 mg, 0.019 mmol) at room temperature under N₂. Thereaction was cooled to room temperature, and extracted with ethylacetate (10 mL×2). The organic layers were washed with brine (10 mL),and dried over sodium sulfate and concentrated to give a crude residue,which was purified by column chromatography to give the title compound(40 mg, 32%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 10.0 (s, 1H),8.13 (s, 1H), 7.51 (d, 2H), 7.40 (d, 2H), 7.19 (d, 1H), 3.63 (s, 2H),1.36 (s, 6H).

Step 44,6-difluoro-5-[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]-1H-indole-3-carboxylicacid

To a solution of4,6-difluoro-5-[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]-1H-indole-3-carbaldehyde(40 mg, 0.122 mmol) in acetonitrile (2.3 mL), t-butanol (2.3 mL) and2-methyl-2-butene (1.5 mL) was added a solution of sodium chlorite (164mg, 2.43 mmol) and sodium dihydrogen phosphate (335 mg, 2.43 mmol) inwater (2.3 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 18 h. The reaction was quenched with a solution ofsodium sulfite (337 mg, 2.68 mmol) in water (5.0 mL), and extracted withethyl acetate (10 mL×3). The organic layers were washed with brine (10mL) and dried over sodium sulfate, filtered and concentrated to give acrude residue, which was purified by reverse phase HPLC to give thetitle compound (14.6 mg, 42%) as a white solid.

MS (AP+) 367.8 (M+Na)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.00 (s, 1H), 7.51 (d,2H), 7.42 (d, 2H), 7.13 (d, 1H), 3.64 (s, 2H), 1.37 (s, 6H)

Example 275-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-6-methyl-1H-indole-3-carboxylicacid

Step 1 5-bromo-6-methyl-1H-indole-3-carbaldehyde

Phosphorus oxychloride (0.73 g, 4.79 mmol) and DMF (5.0 mL) were mixedtogether and stirred for 5 min. A solution of 5-bromo-6-methyl-1H-indole(500 mg, 2.39 mmol) in DMF (3.0 mL) was added to the solution slowly andcomplete solid was formed which stopped stirring. The solution wasadjusted to pH=10 with 1 N NaOH, then heated to 100° C. for 1 min. Thereaction was cooled to room temperature. The precipitated solids werefiltered and dried to give the title compound (480 mg, 85%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (s, 1H), 9.88 (s, 1H), 8.28 (s,1H), 8.23 (s, 1H), 7.49 (s, 1H), 2.44 (s, 3H).

Step 25-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-6-methyl-1H-indole-3-carbaldehyde

A solution of 5-bromo-6-methyl-1H-indole-3-carbaldehyde (200 mg, 0.84mmol) and{1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]cyclopropyl}methanol(242 mg, 0.93 mmol) in toluene (6 mL) and EtOH (2.0 mL) was added to asolution of potassium carbonate (350 mg, 2.52 mmol) in water (1.0 mL)and Pd(dppf)Cl₂ (34 mg, 0.042 mmol) at room temperature under N₂. TLC(petroleum ether/EtOAc=1:1) showed the reaction was complete. Thereaction was cooled to room temperature, and extracted with ethylacetate (20 mL×3). The organic layers were washed with brine (20 mL),dried over sodium sulfate and concentrated to give a crude ARRR!!!!,which was purified by column chromatography to give the title compound(190 mg, 74%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 9.83 (s, 1H),8.05 (s, 1H), 7.93 (s, 1H), 7.41 (d, 2H), 7.37 (s, 1H), 7.27 (d, 2H),3.69 (s, 2H), 2.31 (s, 3H), 0.89 (d, 4H).

Step 35-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-6-methyl-1H-indole-3-carboxylicacid

To a solution of5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-6-methyl-1H-indole-3-carbaldehyde(50 mg, 0.164 mmol) in acetonitrile (3.3 mL), t-butanol (3.3 mL) and2-methyl-2-butene (2.2 mL) was added a solution of sodium chlorite (221mg, 3.28 mmol) and sodium dihydrogen phosphate (452 mg, 3.28 mol) inwater (3.3 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 18 h. TLC (petroleum ether/EtOAc=1:1) showed most of thestarting material was consumed. The reaction was quenched with asolution of sodium sulfite (455 mg, 3.61 mmol) in water (3.0 mL), andextracted with ethyl acetate (20 mL×3). The organic layers were washedwith brine (20 mL) and dried over sodium sulfate, filtered andconcentrated to give a crude residue, which was purified by reversephase HPLC to give the title compound (9.3 mg, 18%) as a white solid. MS(AP+) 322.1 (M+1)⁺. ¹H NMR (400 MHz, CD₃OD) 7.89 (s, 1H), 7.82 (s, 1H),7.40 (d, 2H), 7.30 (s, 1H), 7.28 (d, 2H), 3.69 (s, 2H), 2.30 (s, 3H),0.89 (m, 4H).

Example 284,6-difluoro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carboxylic acid

Step 1 3-(4-bromophenoxy)propan-1-ol

To a solution of 4-bromophenol (10 g, 58 mmol) in DMF (10 mL) was added3-bromopropan-1-ol (9.6 g, 69 mmol) and potassium carbonate (13.6 g, 98mmol). The mixture was stirred at room temperature for 12 h. LCMS showedthe reaction was almost complete. The mixture was partitioned betweenwater and ethyl acetate (20 mL×3), The combined organics were dried andconcentrated to give the title compound that was used in the next stepwithout further purification (14.7 g, quant). ¹H NMR (400 MHz, CD₃OD) δ7.36 (d, 2H), 6.84 (d, 2H), 4.05 (t, 2H), 3.72 (t, 2H), 1.96 (m, 2H).

Step 2 3-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy)propan-1-ol

To a suspension of oven dried potassium acetate (27.6 g, 281 mmol) and3-(4-bromophenoxy)propan-1-ol (13.0 g, 56.3 mmol) in dry dioxane (100mL) was added bis(neopentylglycolato) diboron (14.0 g, 61.9 mmol). Thesolvent was degassed by passing nitrogen through the system for 10 min.Pd(dppf)Cl₂ (1.0 g, 1.3 mmol) was added and the reaction heated to 90°C. The reaction was cooled, diluted with ethyl acetate then filteredthrough celite and stripped. Residue was then filtered through a plug ofsilica gel with ethyl acetate then concentrated in vacuo. The residuewas then adsorbed onto a 25 g column with dichloroethane and purified bysilica gel chromatography (100 g, 20-60% EtOAc/Heptane). The one majorpeak was isolated to give the title product as a yellow oil (17.78 g,quant.) that was used without any further purification. GCMS: 264

Step 34,6-difluoro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carbaldehyde

To the slurry of 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde was added2 M potassium carbonate (0.7 mL) and the mixture was stirred at roomtemperature for 5 min. Then3-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy)propan-1-ol (120 mg,0.46 mmol) and Pd(dppf)Cl₂ (20 mg) was added to the reaction. Thereaction was heated to 90° C. for 30 min. Solvent was removed underreduced pressure to give a residue, which was purified by silica gelchromatography (petroleum ether/ethyl acetate=4:1) to give the titlecompound (30 mg, 20%) as a yellow solid.

Step 44,6-difluoro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carboxylic acid

To a mixture of4,6-difluoro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carbaldehyde (30mg, 0.1 mmol) in ACN/t-butanol=1/1 (2 mL) was added 2-methyl-2-butene(0.5 mL) and cooled to 0° C. and added the aqueous solution of sodiumchlorite (180 mg, 0.5 mL) and sodium dihydrogen phosphate (270 mg, 2mmol) in water (0.5 mL) dropwise via additional funnel. The reaction wasstirred at room temperature for 10 h. The reaction was quenched withsodium sulfite. The mixture was partioned between dichloromethane andwater. The combined organics were concentrated to give a residue, whichwas purified by reverse phase HPLC to give the title compound (15 mg,43%) as a white solid. MS (AP+) 348.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ7.74 (s, 1H), 7.36 (d, 2H), 7.03-6.98 (m, 3H), 4.14 (t, 2H), 3.77 (t,2H), 2.04-2.01 (m, 2H).

Example 29 6-chloro-5-(3-methoxyphenyl)-1H-indole-3-carboxylic acid

Step 1 6-chloro-5-(3-methoxyphenyl)-1H-indole-3-carbaldehyde

To a solution of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (300 mg, 2mmol) in dioxane/DMF=1/1 (4 mL) was added (3-methoxyphenyl)boronic acid(463 mg, 1.8 mmol), potassium carbonate (828 mg, 6 mmol) in water (1mL), and Pd (dppf)Cl₂ (50 mg) in a microwave vial. The sealed vial wasirradiated in the microwave on a Biotage Smith Synthesizer at 110° C.for 30 min, TLC (petroleum ether/ethyl acetate=1:1) showed the reactionwas complete. The solvent was removed in vacuo and the mixture waspartitioned between ethyl acetate and water. The combined organics weredried over sodium sulfate, concentrated in vacuo, and purified bycombi-flash to give the title compound (270 mg, 47%) as a yellow solid

¹H NMR (400 MHz, CD₃OD) δ 9.90 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.62(s, 1H), 7.36-7.34 (m, 1H), 7.01-6.93 (m, 3H), 3.84 (s, 3H)

Step 2 6-chloro-5-(3-methoxyphenyl)-1H-indole-3-carboxylic acid

To a solution of 6-chloro-5-(3-methoxyphenyl)-1H-indole-3-carbaldehyde(100 mg, 0.35 mmol) in ACN/t-butanol=1/1 (4 mL) was added2-methyl-2-butene (1 mL) at 0° C. and stirred 10 min. Then an aqueoussolution of sodium chlorite (315 mg, 3.5 mmol) and sodium dihydrogenphosphate (480 mg, 3.5 mmol) in water (1 mL) was added to the systemdropwise. The reaction was stirred at room temperature for 10 h. Thereaction was quenched with sodium sulfite. The mixture was partitionedbetween DCM and water. The combined organics were dried and concentratedto give a residue, which was purified by reverse phase HPLC to give thetitle compound (40 mg, 38%) as a white solid. MS (AP−) 300.1 (M−1)⁻. ¹HNMR (400 MHz, CD₃OD) δ 8.01 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.33(t, 1H), 7.01-6.97 (m, 2H), 6.93 (dd, 1H), 3.84 (m, 1H).

Example 306-chloro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carboxylic acid

Step 1 6-chloro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carbaldehyde

To a solution of3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]propan-1-ol (4.9 g,18.6 mmol) in ethanol (25 ml) was added5-bromo-6-chloro-1H-indole-3-carbaldehyde (4.0 g, 15 mmol) followed bytoluene (50 ml) and 2 N aq. potassium carbonate (26.3 ml, 52.6 mmol).Nitrogen was bubbled though the solution for 15 min, then Pd(dppf)Cl₂(0.46 g, 0.62 mol) was added and reaction heated to 100° C. Anadditional portion of3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]propan-1-ol (1.0 g)in ethanol (4 ml) was added and heating continued for 30 min. Thereaction was allowed to cool to room temperature and stirred for 3 days.The reaction was partitioned between water and EtOAc and stirred. Thelayers were separated and the organic layers were washed with waterwhich resulted in a thick emulsion. The emulsion was filtered throughcelite to attempt to break the emulsion which had limited effect. Uponstanding, emulsion was reduced. Layers were separated and organic washedwith brine, dried over sodium sulfate, filtered and stripped. Residuewas mostly dissolved in MeOH, filtered to remove solids then adsorbedonto silica gel then purified by silica gel chromatography (30-100%EtOAc/Heptane). The second peak was isolated to afford the titlecompound (2.2 g, 43%) as a yellow solid that was taken on to the nextreaction without further purification.

MS (AP+) 330.2 (M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (br. s, 1H),9.94 (s, 1H) 8.37 (d, 1H), 8.02 (s, 1H), 7.68 (s, 1H), 7.34 (d, 2H),7.01 (d, 2H), 4.57 (t, 1H), 4.09 (t, 2H), 3.59 (q, 2H), 1.90 (quin, 2H).

Step 2 6-chloro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carboxylicacid

To an ice cooled thin suspension of6-chloro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carbaldehyde (2.2 g,6.7 mmol) in a mixture of THF (60 ml) and t-BuOH (60 ml) was added2-methyl-2-butene (22 mL, 210 mmol). Separately, sodium chlorite (5.6 g,66.7 mmol) and sodium phosphate monohydrate (monobasic, 9.2 g, 66.7mmol) were dissolved in water (50 mL) and added to the original solutionvia addition funnel over 30 min. The clear mixture was warmed to roomtemperature and stirred for 20 hours. The mixture was cooled to 0° C.and more 2-Me-2-butene (10 mL) was added, followed by slow addition of asolution of sodium chlorite (2.8 g) and sodium phosphate (monobasic andmonohydrate, 4.6 g) in water (18 mL) then stirred at room temperaturefor 4 hrs. Methyl t-butyl ether (100 ml) and heptane (100 ml) were addedand the organic phase was separated and washed with 0.3 M aqueous sodiumhydroxide. The aqueous solution was acidified with 1 M HCl and extractedwith a mixture of 150 ml of ethyl acetate and 50 ml of heptane. Theextract was washed with brine, dried over sodium sulfate, andconcentrated. The crude residue was dissolved in acetone and loaded ontosilica gel and solvents were removed. The material absorbed on silicagel was placed on silica gel and flash column chromatography (40% to 70%acetone/heptanes) was used to provide 1.5 g of a tan solid. The solidwas dissolved in MeOH at 60° C. Water (10 ml) was added dropwise untilsolids almost persisted. After 5 min, solids formed and the mixture wasallowed to cool slowly and stirred for 2 days at room temperature.Solids were collected by vacuum filtration and rinsed with a 50%MeOH/Water solution then dried over a nitrogen ram for 1 hour then in adrying pistol for 2 hours to afford the title compound (1.23 g, 53%) asa crystalline white solid. Melting point: 209.3-209.6. MS (AP−) 344.1(M−H)⁻. ¹H NMR (400 MHz, DMSO-d₆) δ 12.10 (s, 1H), 11.92 (d, 1H), 8.07(d, 1H), 7.93 (s, 1H), 7.61 (s, 1H), 7.34 (d, 2H), 7.00 (d, 2H), 4.56(t, 1H), 4.09 (t, 2H), 3.59 (q, 2H), 1.89 (quin, 2H).

Example 31 6-Chloro-5-(4-ethoxyphenyl)-1H-indole-3-carboxylic acid

Step 1 6-Chloro-5-(4-ethoxyphenyl)-1H-indole

A solution of 5-bromo-6-chloro-1H-indole (5.92 g, 25.7 mmol), sodiumcarbonate (5.45 g, 51.4 mmol) and (4-ethoxyphenyl)boronic acid (5.12 g,30.8 mmol) in EtOH/water/toluene (30 mL, each) was degassed with N₂ for5 minutes, treated with tetrakis(triphenylphosphine)palladium (1.8 g,16.57 mmol) and degassed for an additional 5 minutes. The reactionmixture was heated to reflux under N₂ for 16 hours. The reaction mixturewas cooled to room temperature, poured into dilute NH₄Cl solution (200mL), and extracted with CH₂Cl₂ (3×100 mL). The combined organic layerswere washed with brine (100 mL), dried over Na₂SO₄ and concentrated invacuo. The crude material was purified by flash chromatography (9-25%EtOAc/petroleum ether) to afford the title compound (6.03 g, 86%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (br, 1H), 7.50 (s, 1H), 7.43(s, 1H), 7.33 (d, 2H), 7.15 (m, 1H), 6.89 (d, 2H), 6.46 (s, 1H), 4.02(q, J=7.00 Hz, 2H), 1.36 (t, J=7.00 Hz, 3H).

Step 22,2,2-Trichloro-1-(6-chloro-5-(4-ethoxyphenyl)-1H-indol-3-yl)ethanone

To a solution of 6-chloro-5-(4-ethoxyphenyl)-1H-indole (500.0 mg, 1.84mmol) in anhydrous THF (5 mL) was added pyridine (436.0 mg, 5.52 mmol)and trichloroacetyl chloride (10 mL) at 0° C. under N₂. The reactionmixture was stirred at room temperature under N₂ for 12 hours. Themixture was poured into 0.5 N HCl (200 mL) and extracted with EtOAc(3×100 mL). The combined organic layers were washed with brine (100 mL),dried over Na₂SO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography (9-25% EtOAc/petroleum ether:EtOAc) togive the title compound (70.0 mg, 9%) as a green solid. ¹H NMR (400 MHz,CDCl₃) δ 8.80 (br, 1H), 8.40 (s, 1H), 8.36 (d, J=3.2 Hz, 1H), 7.59 (s,1H), 7.42 (d, 2H), 6.97 (d, 2H), 4.12 (q, J=7.00 Hz, 2H), 1.45 (t,J=7.00 Hz, 3H).

Step 3 6-Chloro-5-(4-ethoxyphenyl)-1H-indole-3-carboxylic acid

To a solution of2,2,2-trichloro-1-(6-chloro-5-(4-ethoxyphenyl)-1H-indol-3-yl)ethanone(70.0 mg, 0.17 mmol) in DME (1 mL) was added 1 N KOH (0.71 mmol, 0.71mL). The reaction mixture was stirred at room temperature for 12 hours,and concentrated in vacuo. The crude material was diluted with water (5mL), and acidified to pH 2.5 with 1 N HCl to form a white precipitate.The precipitate was filtered, washed with water (20 mL) and dried undervacuum to provide the title compound (37 mg, 70%) as an off-white solid.

MS (ES+) 315.9 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.21 (br. s., 1H),12.00 (s, 1H), 8.13 (d, J=2.80 Hz, 1H), 7.99 (s, 1H), 7.40 (d, J=8.80Hz, 1H), 7.06 (d, J=8.80 Hz, 2H), 4.13 (q, J=6.80 Hz, 2H), 1.43 (t,J=6.80 Hz, 3H).

Example 32 6-Cyano-5-(4-methoxyphenyl)-1H-indole-3-carboxylic acid

Step 1 4′-Methoxy-5-methyl-4-nitro-biphenyl-2-carbonitrile

A mixture of 2-bromo-4-methyl-5-nitro-benzonitrile (522.0 mg, 2.17mmol), 4-methoxyphenyl boronic acid (329.0 mg, 2.17 mmol) and 2 Naqueous potassium carbonate (6.56 mL, 13.1 mmol) in EtOH (6 mL) andtoluene (3 mL) was degassed with N₂ for 5 minutes, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (180.0 mg,0.22 mmol), and degassed with N₂ for an additional 5 minutes. Thereaction mixture was sealed and heated to 80° C. for 3 hours. Thereaction was cooled to room temperature and the layers were separated.The organic layer was filtered and the solids were air dried to give thetitle compound (145 mg). The filtrate was concentrated in vacuo and theresidue was purified by flash chromatography (25-75% EtOAc/heptane) togive the title compound (337 mg). The two lots of the title compoundwere combined (482 mg, 83% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s,1H), 7.78 (s, 1H), 7.63 (d, J=8.78 Hz, 2H), 7.14 (d, J=8.59 Hz, 2H),3.85 (s, 3H), 2.64 (s, 3H).

Step 2 5-(4-Methoxy-phenyl)-1H-indole-6-carbonitrile

A mixture of 4′-methoxy-5-methyl-4-nitro-biphenyl-2-carbonitrile (118.0mg, 0.44 mmol) and tris(dimethylamino) methane (128.0 mg, 0.88 mmol) intoluene (15 mL) was heated to reflux for 2 hours. The reaction mixturewas concentrated in vacuo. The resulting residue was dissolved in EtOH(1 mL) and water (0.10 mL), and treated with iron powder (64.0 mg, 1.15mmol), followed by concentrated HCl (28.0 mg, 0.29 mmol). The reactionmixture was heated to reflux for an additional 16 hours, and quenchedwith 1 N aqueous NaOH (0.288 mL). The solution was filtered throughcelite and rinsed with EtOH (10 mL). The filtrate was concentrated invacuo to give the title compound (35 mg, 49% yield). MS (ES−) 247.1(M−1)⁻. ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (s, 1H), 7.68 (d, J=2.73 Hz,1H), 7.66 (s, 1H), 7.48 (d, J=8.59 Hz, 2H), 7.05 (d, J=8.59 Hz, 2H),6.58 (d, J=2.73 Hz, 1H), 3.82 (s, 3H).

Step 3 3-Formyl-5-(4-methoxy-phenyl)-1H-indole-6-carbonitrile

Phosphorous oxychloride (84.3 mg, 0.54 mmol) was added to DMF (1 mL) at0° C. and the reaction mixture was stirred for 15 minutes. To thissolution was added 5-(4-methoxy-phenyl)-1H-indole-6-carbonitrile (150.0mg, 0.60 mmol) in DMF (1 mL) and the reaction mixture was stirred at 40°C. for 1 hour. The reaction mixture was cooled to room temperature,treated with additional phosphorous oxychloride (84.3 mg, 0.54 mmol) andstirred at 45° C. for an additional hour. The reaction mixture wascooled to room temperature, and quenched with water (10 mL). Thesolution was concentrated in vacuo, and the residue was partitionedbetween water (10 mL) and EtOAc (10 mL). The layers were separated andthe organic layer was concentrated in vacuo. The crude material wasslurried in CH₂Cl₂, and the resulting solid was filtered and air driedto give the title compound (85 mg, 51% yield). MS (ES⁻) 275.1 (M−1)⁻. ¹HNMR (400 MHz, DMSO-d₆) δ 12.63 (br. s., 1H), 10.00 (s, 1H), 8.58 (d,J=3.12 Hz, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.51 (d, J=8.59 Hz, 2H),7.09 (d, J=8.80 Hz, 2H), 3.83 (s, 3H).

Step 4 6-Cyano-5-(4-methoxyphenyl)-1H-indole-3-carboxylic acid

A solution of sodium chlorite (8.1 mg, 0.072 mmol) in water (2 mL) wasadded dropwise to a solution of3-formyl-5-(4-methoxy-phenyl)-1H-indole-6-carbonitrile (50.0 mg, 0.18mmol), sodium phosphate monohydrate (5.60 mg, 0.04 mmol) and 25%hydrogen peroxide (25.9 mg, 0.19 mmol) in MeCN (2 mL) and water (1 mL)at 0° C.

The reaction mixture was stirred at 0° C. for 30 minutes, and warmed toroom temperature. Additional sodium chlorite (16.2 mg, 0.144 mmol) andMeCN (5 mL) were added, and the reaction mixture was stirred at roomtemperature for another 16 hours. The reaction was quenched with sodiumsulfite (46.6 mg, 0.362 mmol) and acidified with concentrated HCl (1 mL)to form precipitates. The solid was filtered, washed with water (5 mL)and air dried to give the title compound (14 mg, 26% yield). MS (ES⁻)291.1 (M−1)⁻. ¹H NMR (400 MHz, DMSO-d₆) δ 12.35 (br. s., 1H), 12.14 (br.s, 1H), 8.29 (d, J=2.73 Hz, 1H), 8.07 (s, 1H), 8.04 (s, 1H), 7.50 (d,J=8.20 Hz, 2H), 7.08 (d, J=8.39 Hz, 2H), 3.83 (s, 3H).

Example 33 6-Chloro-5-(4-methoxy-phenyl)-1H-indole-3-carboxylic acid

Step 1 6-Chloro-5-(4-methoxy-phenyl)-1H-indole

A mixture of 5-bromo-6-chloro-1H-indole (60.3 g, 261.6 mmol),4-methoxyphenylboronic acid (54.8 g, 353 mmol), 4 N aqueous potassiumcarbonate (262 mL, 1.05 mol) in toluene (750 mL) and EtOH (250 mL) wasdegassed with N₂ for 35 minutes and treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.41 g,7.85 mmol). The reaction mixture was placed in a pre-heated oil bath at105° C. and stirred for 1.5 hours. The reaction was removed from the oilbath, quickly cooled to room temperature and poured into EtOAc (2 L) and0.5 N HCl (500 mL). The organic layer was separated, washed with 0.5 NNaOH (1×500 mL) followed by saturated brine (1×500 mL), dried over MgSO₄and concentrated in vacuo to afford a black oil. The oil was passedthrough a pad of silica gel, eluting with 15% EtOAc/heptane. Productfractions were concentrated to afford 55.3 g gray solid. The solid wastriturated in 1:1 ether/heptane (50 mL) and filtered to afford the titlecompound (25 g, 37% yield) as a cream-colored solid. MS (ES+) 258.5(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (br. s., 1H), 7.58 (s, 1H), 7.52(s, 1H), 7.42 (d, J=8.78 Hz, 2H), 7.24 (t, J=2.68 Hz, 1H), 6.98 (d,J=8.78 Hz, 2H), 6.55 (br. s., 1H), 3.88 (s, 3H).

Step 2 6-Chloro-5-(4-methoxy-phenyl)-1H-indole-3-carbaldehyde

6-Chloro-5-(4-methoxy-phenyl)-1H-indole (25.0 g, 97 mmol),(chloromethylene)dimethyliminium chloride (18.8 g, 147 mmol) and MeCN(100 mL) were stirred at room temperature for 20 minutes. To theresulting bright yellow slurry was added 1 N NaOH (400 mL, 400 mmol) andwater (400 mL). The reaction mixture was heated to 100° C. for 45minutes, then cooled to 0° C. The slurry was filtered, and the collectedsolid was washed with water and air dried to afford the title compoundas a yellow solid. MS (ES+) 286.5 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ10.06 (s, 1H), 8.74 (br. s., 1H), 8.29 (s, 1H), 7.87 (d, J=2.93 Hz, 1H),7.58 (s, 1H), 7.42 (d, J=8.54 Hz, 2H), 6.98 (d, J=8.54 Hz, 2H), 3.88 (s,3H)

Step 3 6-Chloro-5-(4-methoxy-phenyl)-1H-indole-3-carboxylic acid

To a solution of 6-chloro-5-(4-methoxy-phenyl)-1H-indole-3-carbaldehyde(27.7 g, 97 mmol) in MeCN (400 mL), tert-butanol (400 mL) and2-methyl-2-butene (400 mL, 3.76 mol) at 0° C. was added a solution ofsodium chlorite (82.0 g, 970 mmol) and sodium phosphate monobasichydrate (134.0 g, 970 mmol) in water (400 mL) dropwise over 20 minutes.The ice bath was removed and the mixture was stirred at roomtemperature. At the 16-hour and 20-hour time points, additional2-methyl-2-butene (200 mL, 1.88 mol) was added, followed by solid sodiumchlorite (82.0 g, 970 mmol) and solid sodium phosphate monobasic hydrate(134.0 g, 970 mmol). After a total of 22 hours, the reaction mixture waspoured into a solution of saturated NH₄Cl (800 mL) and water (200 mL),then extracted with EtOAc (4×500 mL). The combined organic layers weredried over MgSO₄, and concentrated in vacuo to afford 62 g of amustard-colored semi-solid. This solid was triturated in CHCl₃ (70 mL),filtered and dried under high vacuum to afford 18.5 g pale yellow solid.The solid was stirred in EtOAc (50 mL) overnight at 55° C., thenfiltered hot and washed with room temperature EtOAc to afford the titlecompound (19.5 g, 63% for 2 steps) as a pale yellow solid. MS (ES+)302.5 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.10 (br. s., 1H), 11.93 (br.s., 1H), 8.07 (d, J=2.68 Hz, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.35 (d,J=8.54 Hz, 2H), 7.01 (d, J=8.78 Hz, 2H), 3.81 (s, 3H).

Example 34 6-Fluoro-5-(4-methoxy-phenyl)-1H-indole-3-carboxylic acid

Step 1 6-Fluoro-5-(4-methoxy-phenyl)-1H-indole

A mixture of 5-bromo-6-fluoro-1H-indole (600.0 mg, 2.80 mmol),4-methoxyphenyl boronic acid (426.0 mg, 2.80 mmol), 2 N aqueouspotassium carbonate (8.49 mL, 16.98 mmol) in EtOH (8 mL) and toluene (3mL) were degassed with N₂ for 5 minutes, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (180.0 mg,0.22 mmol), and degassed for an additional 5 minutes. The reactionmixture was sealed and heated to 80° C. for 16 hours. The reaction wascooled to room temperature and the layers were separated. The organiclayer was concentrated in vacuo and the crude material was purified byflash chromatography (25-75% EtOAc/heaptane) to give the title compound(147 mg, 22% yield). MS (ES⁺) 242.3 (M+1)⁺.

Step 2 6-Fluoro-5-(4-methoxy-phenyl)-1H-indole-3-carbaldehyde

Phosphorous oxychloride (185.0 mg, 1.20 mmol) was added to DMF (2 mL) at0° C. and the reaction mixture was stirred for 15 minutes. To thissolution was added 6-fluoro-5-(4-methoxy-phenyl)-1H-indole (147.0 mg,0.61 mmol) in DMF (2 mL) and the reaction mixture was stirred at 95° C.for 20 minutes. The reaction mixture was cooled to room temperature,treated with 1 N aqueous NaOH (3 mL) and heated to 100° C. for 1 minute.The reaction mixture was cooled to room temperature and filtered. Thecollected solids were air dried to give the title compound (106 mg, 65%yield). MS (ES⁺) 270.2 (M+1)⁺.

Step 3 6-Fluoro-5-(4-methoxy-phenyl)-1H-indole-3-carboxylic acid

To a solution of 6-fluoro-5-(4-methoxy-phenyl)-1H-indole-3-carbaldehyde(106.0 mg, 0.39 mmol) in MeCN (5 mL) and water (3 mL) was added sodiumphosphate monobasic hydrate (12.3 mg, 0.087 mmol), 25% hydrogen peroxide(56.3 mg, 0.41 mmol) and sodium chlorite (44.5 mg, 0.39 mmol). Thereaction mixture was stirred for one hour at room temperature andadditional MeCN (5 mL) and sodium chlorite (44.5 mg, 0.39 mmol) wereadded. The reaction mixture was heated to 50° C. for one hour, cooled toroom temperature and stirred for another 16 hours. The reaction wasquenched with sodium sulfite (405.0 mg, 3.15 mmol) and acidified with 3N HCl (1 mL). The reaction solution was partially concentrated in vacuo,and extracted with EtOAc (10 mL). The organic layer was concentrated invacuo and purified by reverse phase HPLC (Waters Sunfire C18 19×100, 5μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFAin MeCN (v/v); Gradient: 80:20 A:B linear to 40:60 A:B in 8.5 min to100% B to 9.0 min, hold at 100% B from 9.0 to 10.0 min. Flow: 25 mL/min)to give the title compound (6.8 mg, 6% yield). MS (ES⁺) 286.2 (M+1)⁺.Retention time=2.73 minutes (Waters Atlantis dC18 4.6×50, 5 μm; Mobilephase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN(v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95A:B to 5.0 min. Flow: 2 mL/min).

Example 355-[4-(1-hydroxycyclobutyl)phenyl]-6-methyl-1H-indole-3-carboxylic acid

Step 15-[4-(1-hydroxycyclobutyl)phenyl]-6-methyl-1H-indole-3-carbaldehyde

A mixture of dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphane (62.8mg, 0.153 mmol), palladium acetate (13.7 mg, 0.061 mmol), tribasicpotassium phosphate monohydrate (566 mg, 2.46 mmol), and methyl boronicacid (184 mg, 3.07 mmol) was sealed in a microwave tube and evacuatedand backfilled with nitrogen three times. Deoxygenated 1,4-dioxane (1.5mL) was added and the mixture was stirred vigorously at room temperaturefor one hour. A solution of6-chloro-5-[4-(1-hydroxy-cyclobutyl)-phenyl]-1H-indole-3-carbaldehyde(400 mg, 1.23 mmol) in 1,4-dioxane (2.5 mL) was degassed with nitrogenfor 10 minutes then added to the reaction mixture. The reaction mixturewas heated at 120° C. for three hours under microwave irradiation, andthen allowed to stir at room temperature for 12 hours. The reactionmixture was poured into saturated ammonium chloride solution (20 mL) andextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over sodium sulfate, filtered and evaporated. Flash silica gelchromatography was performed on the crude product utilizing a solventsystem of heptanes/ethyl acetate (9:1 to 1:1) to give the titlecompound. MS (ES+) 306.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 9.86 (s, 1H),8.06 (s, 1H), 7.95 (s, 1H), 7.55 (d, 2H), 7.38 (s, 1H), 7.36 (d, 2H),2.61 (m, 2H), 2.39 (m, 2H), 2.34 (s, 3H), 2.05 (m, 1H), 1.75 (m, 1H).

Step 2 5-[4-(1-hydroxycyclobutyl)phenyl]-6-methyl-1H-indole-3-carboxylicacid

A partial suspension of5-[4-(1-hydroxycyclobutyl)phenyl]-6-methyl-1H-indole-3-carbaldehyde (130mg, 0.426 mmol) in tetrahydrofuran (3 mL) and tert-butanol (3 mL) wastreated with 2-methyl-2-butene (2.27 mL, 21.4 mmol) followed by asolution of sodium chlorite (538 mg, 6.4 mmol) and sodium phosphatemonobasic hydrate (904 mg, 6.5 mmol) in water (2 mL) via glass pipet atroom temperature. The reaction mixture was stirred vigorously at roomtemperature for 62 hours, and was poured into half-diluted saturatedaqueous ammonium chloride solution (50 mL). The product was extractedwith ethyl acetate (3×60 mL), and the combined organic layers were driedover sodium sulfate, filtered and evaporated. The crude product waspurified using reverse-phase chromatography to give the title compound.

MS (ES−) 320.2 (M−H)⁻. ¹H NMR (600 MHz, DMSO-d₆) δ 7.95 (d, J=3.1 Hz,1H), 7.79 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.35 (s, 1H), 7.31 (d, J=8.0Hz, 2H), 5.50 (s, 1H), 2.48-2.41 (m, 2H), 2.35-2.26 (m, 5H), 1.99-1.88(m, 1H), 1.74-1.62 (m, 1H).

Example 366-chloro-5-[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]-1H-indole-3-carboxylicacid

Step 15-[4-(1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropan-2-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (549 mg,1.6 mmol), oven-dried potassium acetate (666 mg, 6.79 mmol), and[2-(4-bromophenyl)-2-methylpropoxy](tert-butyl)dimethylsilane (503 mg,1.46 mmol) in 1,4-dioxane (4.88 mL) was degassed for 10 minutes, thentreated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(100 mg, 0.137 mmol). The mixture was sealed in a microwave vial andheated to 110° C. in a microwave for 1 hour. The black reaction mixturewas then diluted with heptane (50 mL) and filtered through a plug ofsilica gel, eluting with 4:1 heptane/ethyl acetate. The filtrate wasevaporated in vacuo to give a dark semi solid (638 mg). The crudeproduct was dissolved in toluene (4 mL). 2.38 mL of this solution wasdiluted with ethanol (1 mL) and treated with 2 M aqueous potassiumcarbonate solution (1.16 mL, 2 mmol), and5-bromo-6-chloro-1H-indole-3-carbaldehyde (150 mg, 0.58 mmol). Themixture was degassed with nitrogen for 15 minutes, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.7 mg,0.046 mmol) and heated in an oil bath at 100° C. for 3 hours. Thereaction mixture was treated with an additional 0.35 mL of the boronatesolution prepared above and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg) andheated at 100° C. for an additional 3 hours. The cooled reaction mixturewas poured into saturated aqueous ammonium chloride solution andextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over sodium sulfate, filtered and evaporated to give a dark oil,which was directly purified using silica gel chromatography (100:0 to6:4 heptane/ethyl acetate) to give the title compound as a white solid(130 mg, 50%). MS (ES−) 440.7 (M−H)⁻. ¹H NMR (500 MHz, CDCl₃) δ 10.07(s, 1H), 8.30 (s, 1H), 7.87 (d, J=2.7 Hz, 1H), 7.58 (s, 1H), 7.46-7.42(m, 4H), 3.59 (s, 2H), 1.37 (s, 6H), 0.88 (s, 9H), −0.02 (s, 6H).

Step 25-[4-(1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropan-2-yl)phenyl]-6-chloro-1H-indole-3-carboxylicacid

A solution of5-[4-(1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropan-2-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde(130 mg, 0.294 mmol) in tetrahydrofuran (2.5 mL) and tert-butanol (2.5mL) was treated with 2-methyl-2-butene (2.19 mL, 20.6 mmol) followed bya solution of sodium chlorite (496 mg, 5.9 mmol) and sodium phosphatemonobasic hydrate (811 mg, 5.9 mmol) in water (2.5 mL) via glass pipetat room temperature. The reaction mixture was stirred vigorously at roomtemperature for 15 hours, and was poured into saturated aqueous ammoniumchloride solution (35 mL). The product was extracted with ethyl acetate(3×25 mL), and the combined organic layers were dried over sodiumsulfate, filtered and evaporated to give the title compound as an amberoil. MS (ES−) 456.6 (M−H)⁻. ¹H NMR (400 MHz, CD₃OD) δ 8.01 (s, 1H), 7.99(d, J=1.2 Hz, 1H), 7.57 (s, 1H), 7.43 (d, 2H), 7.37 (d, 2H), 3.63 (s,2H), 1.36 (s, 6H), 0.86 (s, 9H), −0.05 (s, 6H).

Step 36-chloro-5-[4-(1-hydroxy-2-methylpropan-2-yl)phenyl]-1H-indole-3-carboxylicacid

A solution of5-[4-(1-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpropan-2-yl)phenyl]-6-chloro-1H-indole-3-carboxylicacid (76 mg, 0.17 mmol) in DMF (0.55 mL) was treated with solid cesiumfluoride (507 mg, 3.32 mmol) and stirred at room temperature for onehour. The reaction mixture was then heated at 60° C. for two hours, thenat 50° C. for two hours. The cooled reaction mixture was then pouredinto saturated ammonium chloride solution (20 mL) and extracted withethyl acetate (3×20 mL). The combined organic layers were dried oversodium sulfate, filtered and evaporated to give the title compound as anorange oil. The crude product was dissolved in DMSO (1.8 mL) and 0.9 mLof this solution was purified using reverse-phase chromatography to givethe title Compound. MS (ES−) 342.0 (M−H)⁻. Retention time: 1.61 min;Waters Xbridge dC18 5 μm 4.6×50 mm, 95% H₂O/5% MeCN linear to 5% H₂O/95%MeCN over 4.0 min, HOLD at 5% H₂O/95% MeCN to 5.0 min. (0.03% NH₄OH).Flow: 2.0 mL/min.

Example 37 6-chloro-5-(3,4-dimethoxyphenyl)-1H-indole-3-carboxylic acid

Step 1 methyl 5-bromo-6-chloro-1H-indole-3-carboxylate

A mixture of 5-bromo-6-chloro-1H-indole (15.1 g, 65.5 mmol),tetrahydrofuran (100 mL), pyridine (18.4 mL, 229 mmol) and DMAP (808 mg,6.55 mmol) was cooled to 0° C. and treated with trichloroacetyl chloride(22.1 mL, 197 mmol) dropwise over 30 minutes. The reaction mixture wasstirred at room temperature for 64 hours then cooled to 10° C. Methanol(100 mL) was added dropwise to the reaction mixture over 10 minutes,producing a dark homogenous solution. Potassium carbonate (54.9 g, 393mmol) was then added portion-wise and the ice bath was removed. Stirringwas kept at a vigorous pace and allowed to continue for 2 hours, duringwhich time the reaction turned dark green and produced an exotherm. Thereaction was quenched slowly with 1 M HCl (until acidic pH wasmaintained) and diluted with ethyl acetate. The organic layer was washedwith 1 M HCl. The aqueous layer was back-extracted twice with ethylacetate. The combined organic layers were then washed carefully withsaturated sodium bicarbonate solution followed by brine. The organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo to provide the title compound as a brown solid (18.7 g, 99%).

MS (ES+): 288.0 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (s, 1H), 8.16(s, 1H), 7.72 (s, 1H), 3.81 (s, 3H).

Step 2 methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate

A mixture of methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (10.5 g,36.39 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (9.04 g,40.0 mmol), and oven-dried potassium acetate (17.9 g, 182 mmol), in1,4-dioxane (170 mL) was degassed with nitrogen for 10 minutes, thentreated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(1.6 g, 2.18 mmol). The reaction mixture was heated at 110° C. withstirring for 3 h. The reaction was then cooled to room temperature andfiltered through celite, eluting with ethyl acetate. The filtrate wasconcentrated in vacuo then placed on a pad of silica gel and eluted withethyl acetate. The filtrate was evaporated in vacuo and loaded onto asilica gel column with a minimal amount of methylene chloride and elutedwith ethyl acetate/heptane (1:4 to 1:1) to provide the title compound(5.6 g, 48%) as a tan solid. MS (ES+) 254.1 (M+H)⁺ (M=RB(OH)₂ on LCMS).¹H NMR (500 MHz, DMSO-d₆) δ 11.98 (br. s., 1H), 8.29 (s, 1H), 8.10 (d,J=2.93 Hz, 1H), 7.46 (s, 1H), 3.80 (s, 3H), 3.79 (s, 4H), 1.01 (s, 6H).

Step 3 methyl 6-chloro-5-(3,4-dimethoxyphenyl)-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(100 mg, 0.31 mmol), 4-bromoveratrole (83 mg, 0.37 mmol), and aqueouspotassium carbonate solution (2 M, 0.62 mL, 1.24 mmol) in toluene (1.8mL) and ethanol (0.6 mL) was degassed with nitrogen for 5 minutes thentreated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(13.8 mg, 0.016 mmol). The reaction mixture was heated to 110° C. for2.5 h. The reaction was cooled to room temperature and poured into waterand ethyl acetate. The layers were separated and the aqueous layer wasback-extracted twice with ethyl acetate. The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo.Flash column chromatography was performed on the crude product usingheptanes/ethyl acetate (4:1 to 1:1) to give the title compound (90 mg84%). MS (ES+) 346.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.05 (br. s.,1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 7.04 (d, J=8.29 Hz, 1H),6.98 (s, 1H), 6.93 (d, J=8.29 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.78(s, 3H).

Step 4 6-chloro-5-(3,4-dimethoxyphenyl)-1H-indole-3-carboxylic acid

A solution of methyl6-chloro-5-(3,4-dimethoxyphenyl)-1H-indole-3-carboxylate (75 mg, 0.22mmol), methanol (2.2 mL), and aqueous sodium hydroxide (1 M, 0.75 mL,0.75 mmol) was heated at 75° C. for 24 hours. The reaction was acidifiedwith 1 M HCl to pH=2 then diluted with ethyl acetate. The aqueous layerwas back-extracted twice with ethyl acetate. The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo toprovide a crude solid. The crude product was dissolved in methylenechloride and methanol and silica gel was added. The solvent was removedin vacuo and the crude material adsorbed onto silica was loaded onto acolumn of silica gel and eluted with ethyl acetate (with 0.2% formicacid)/heptanes (1:1 to 1:0) to provide the title compound (17 mg, 24%)as a tan solid.

MS (ES+) 332.1 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.10 (br. s., 1H),11.92 (br. s., 1H), 8.07 (d, J=2.93 Hz, 1H), 7.95 (s, 1H), 7.61 (s, 1H),7.03 (d, J=8.29 Hz, 1H), 6.99 (d, J=1.71 Hz, 1H), 6.93 (dd, J=8.17, 1.83Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H).

Example 38(±)-6-chloro-5-(4-{[trans-2-hydroxycyclopentyl]oxy}phenyl)-1H-indole-3-carboxylicacid

Step 1 (±)-methyl6-chloro-5-(4-{[trans-2-hydroxycyclopentyl]oxy}phenyl)-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(92.6 mg, 0.288 mmol) and (±)-trans-2-(4-bromophenoxy)-cyclopentanol (37mg, 0.14 mmol) in ethanol (0.2 mL), toluene (0.3 mL), and 2 M aqueouspotassium carbonate (0.288 mL, 0.576 mmol) was sealed in a microwavevial and degassed with nitrogen for 10 minutes.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.2 mg,0.014 mmol) was added, and the reaction mixture was resealed and heatedto 90° C. in an oil bath for 1 hour. The reaction mixture was cooled toroom temperature and poured into 0.5 N HCl (10 mL). The product wasextracted with ethyl acetate (3×10 mL), and the combined organic layerswere dried over sodium sulfate, filtered and evaporated. The crudeproduct was purified using silica gel chromatography (4:1 to 1:4heptane/ethyl acetate) to give the title compound (49 mg, 88%) as awhite solid. MS (ES−) 384.2 (M−H)⁻. ¹H NMR (500 MHz, CD₃OD) δ 8.00 (s,1H), 7.98 (s, 1H), 7.57 (s, 1H), 7.34 (d, J=8.5 Hz, 2H), 6.99 (d, J=8.5Hz, 2H), 4.57 (br. s., 1H), 4.26 (br. s., 1H), 3.87 (s, 3H), 2.25-2.15(m, 1H), 2.10-2.02 (m, 1H), 1.91-1.77 (m, 3H), 1.72-1.62 (m, 1H).

Step 2(±)-6-chloro-5-(4-{[trans-2-hydroxycyclopentyl]oxy}phenyl)-1H-indole-3-carboxylicacid

A solution of (±)-methyl6-chloro-5-(4-{[trans-2-hydroxycyclopentyl]oxy}phenyl)-1H-indole-3-carboxylate(32 mg, 0.083 mmol) in methanol (0.845 mL) was treated with 1 N aqueoussodium hydroxide (0.291 mL, 0.291 mmol). The solution was heated to 75°C. in a sealed vial for 24 hours. The cooled reaction mixture was pouredinto 0.3 N HCl (7 mL) and extracted with ethyl acetate (3×5 mL). Thecombined organic layers were dried over sodium sulfate, filtered andevaporated. The crude product was purified using reverse-phasechromatography to give the title compound. MS (ES−) 370.0 (M−H)⁻.Retention time: 1.66 min; Waters Xbridge dC18 5 μm 4.6×50 mm, 95% H₂O/5%MeCN linear to 5% H₂O/95% MeCN over 4.0 min, HOLD at 5% H₂O/95% MeCN to5.0 min. (0.03% NH₄OH). Flow: 2.0 ml/min.

Example 396-chloro-5-{4-[3-(morpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylicacid

Step 1 methyl6-chloro-5-{4-[3-(morpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(45 mg, 0.14 mmol), 4-[3-(4-bromophenoxy)-propyl]-morpholine (42 mg,0.14 mmol) prepared using the procedure in Le Sann, C.; Huddleston, J.;Mann, J. Tetrahedron, 2007, 63, 12903-12911, and 2 M potassium carbonatesolution (0.28 mL, 0.56 mmol) in toluene (0.9 mL) and ethanol (0.3 mL)was degassed with nitrogen for 5 minutes then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.0 mg,0.007 mmol). The reaction vessel was sealed and heated at 110° C. for2.5 h. The cooled reaction mixture was poured into water and ethylacetate. The layers were separated and the aqueous layer wasback-extracted twice with ethyl acetate. The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude product was purified using flash column chromatography elutingwith heptanes/ethyl acetate (4:1 to 0:1) and ethyl acetate/methanol(9:1) to give the title compound (24 mg, 40%). MS (ES+) 429.2 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.37 (br. s., 1H), 7.98 (s, 1H), 7.95 (s, 1H),7.55 (s, 1H), 7.33 (d, J=8.59 Hz, 2H), 6.97 (d, J=8.78 Hz, 2H), 4.11 (t,J=5.95 Hz, 2H), 3.84 (s, 3H), 3.79 (t, J=4.69 Hz, 4H), 2.89-2.97 (m,2H), 2.86 (m, 4H), 2.11 (dt, J=15.42, 5.86 Hz, 2H).

Step 26-chloro-5-{4-[3-(morpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylicacid

A solution of methyl6-chloro-5-{4-[3-(morpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylate(24 mg, 0.056 mmol) in methanol (0.5 mL) and 1 M sodium hydroxide (0.17mL, 0.17 mmol) was heated at 75° C. for 24 hours. The reaction wasacidified with 1 M HCl to pH=2 then diluted with ethyl acetate. Thelayers were separated and the aqueous layer was back-extracted twicewith ethyl acetate. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude product waspurified using reverse-phase chromatography to give the title compoundas the formic acid salt. MS (ES+) 415.129 (M+H)⁺ Retention time: 2.2min; Waters Atlantis dC18 5 μm 4.6×50 mm, 95% H₂O/5% MeCN linear to 5%H₂O/95% MeCN over 4.0 min, HOLD at 5% H₂O/95% MeCN to 5.0 min. (0.05%TFA) Flow: 2.0 mL/min.

Example 406-chloro-5-[4-(1-hydroxycyclobutyl)-2-methylphenyl]-1H-indole-3-carboxylicacid

Step 1 1-(4-bromo-3-methylphenyl)cyclobutanol

To a solution of 2-bromo-4-iodo-1-methylbenzene (0.40 mL, 2.8 mmol) intetrahydrofuran (5 mL) at −78° C. was added n-butyl lithium (2.5 M inhexane, 1.33 mL, 3.33 mmol) dropwise over 15 minutes. The reactionmixture was stirred at −78° C. for 30 minutes, then treated with neatcyclobutanone (0.21 mL, 2.8 mmol) dropwise over 10 minutes. The reactionmixture was stirred at −78° C. for an additional 1.5 hours, then wasquenched with saturated aqueous ammonium chloride solution and extractedwith ethyl acetate (2×). The combined organic layers were dried overmagnesium sulfate, filtered and concentrated in vacuo to afford 800 mgyellow oil, which was purified by flash chromatography (40 g silica,0-100% ethyl acetate/heptane, 17 column volumes). Product fractions werecombined and concentrated in vacuo to afford the title compound as apale pink oil (536 mg, 80% yield). GCMS: 240/242 (m/z). ¹H NMR (500 MHz,CDCl₃) δ 7.51 (d, J=8.29 Hz, 1H), 7.37 (d, J=2.44 Hz, 1H), 7.17 (dd,J=8.29, 2.20 Hz, 1H), 2.45-2.56 (m, 3H), 2.43 (s, 3H), 2.34 (m, 2H),1.96-2.06 (m, 1H), 1.64-1.74 (m, 1H).

Step 2 methyl6-chloro-5-[4-(1-hydroxycyclobutyl)-2-methylphenyl]-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(90 mg, 0.28 mmol), 1-(4-bromo-3-methylphenyl)cyclobutanol (68 mg, 0.28mmol), 4 M aqueous potassium carbonate (0.28 mL, 1.12 mmol), toluene (3mL), and ethanol (1 mL) was sparged with nitrogen for 10 minutes, thentreated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (11 mg, 0.013 mmol). The reaction mixture wasplaced in a pre-heated oil bath at 105° C. and stirred. After 2 hoursthe reaction was cooled to room temperature, diluted with ethyl acetate,washed with water and saturated brine, dried over magnesium sulfate,filtered and concentrated in vacuo to afford 150 mg brown solid, whichwas purified by flash chromatography (0:100 to 70:30 ethylacetate/heptane gradient). Product fractions were combined andconcentrated in vacuo to afford the title compound as a colorless solid(65 mg, 63% yield). MS (ES−) 368.2 (M−H)⁻. ¹H NMR (400 MHz, CDCl₃) δ8.85 (br s, 1H) 7.99 (s, 1H) 7.93 (d, J=2.93 Hz, 1H) 7.52 (s, 1H)7.33-7.43 (m, 2H) 7.20 (d, J=7.81 Hz, 1H) 3.87 (s, 3H) 2.58-2.69 (m, 2H)2.34-2.45 (m, 2H) 2.14 (s, 3H) 2.04-2.11 (m, 1H) 1.69-1.81 (m, 1H).

Step 36-chloro-5-[4-(1-hydroxycyclobutyl)-2-methylphenyl]-1H-indole-3-carboxylicacid

Methyl6-chloro-5-[4-(1-hydroxycyclobutyl)-2-methylphenyl]-1H-indole-3-carboxylate(65 mg, 0.18 mmol) was dissolved in MeOH (3 mL) and 1 N aqueous NaOH (1mL, 1 mmol). The mixture was stirred at 75° C. for 16 hours, was cooledto room temperature and then treated with Aldrich Amberjet 1200H acidicresin (˜1 g). The mixture was stirred for 5 minutes until a pH of 3 wasobtained. The resin was filtered and washed with methanol and thefiltrate was concentrated in vacuo to afford 60 mg colorless solid,which was purified by reversed-phase HPLC (retention time: 1.83 min;Column: Xbridge C18 5 μm 4.6×50 μm; Mobile phase A: 0.03% NH₄OH in water(v/v); Mobile phase B: 0.03% NH₄OH in acetonitrile (v/v); Gradient:95.0% H₂O/5.0% MeCN linear to 5% H₂O/95% MeCN in 5 min, Flow: 25mL/min.) to afford the title compound (36.6 mg, 58% yield). MS (ES−)354.265 (M−H)⁻.

Example 416-chloro-5-[4-(1-hydroxycyclobutyl)-3-methylphenyl]-1H-indole-3-carboxylicacid

Step 1 1-(4-bromo-2-methylphenyl)cyclobutanol

To a solution of 4-bromo-1-iodo-2-methylbenzene (0.24 mL, 1.6 mmol) intetrahydrofuran (5 mL) at −78° C. was added n-butyl lithium (2.5 M inhexane, 0.8 mL, 2.0 mmol) dropwise over 15 minutes. The reaction mixturewas stirred at −78° C. for 30 minutes, treated with neat cyclobutanone(0.12 mL, 1.6 mmol) dropwise over 10 minutes and stirred at −78° C. foran additional 1.5 hours. The reaction was quenched with saturatedaqueous ammonium chloride solution, warmed to room temperature andextracted with ethyl acetate (2×). The combined organic layers weredried over magnesium sulfate, filtered and concentrated in vacuo toafford 500 mg yellow semi-solid, which was purified by flashchromatography (12 g silica, 0-50% ethyl acetate/heptane, 18 columnvolumes). Product fractions were combined and concentrated in vacuo toafford the title compound as a colorless waxy solid (290 mg, 73% yield).GCMS 240/242 (M)⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.23-7.31 (m, 2H), 7.11 (d,J=8.20 Hz, 1H), 2.55-2.64 (m, 2H), 2.28-2.38 (m, 5H), 2.07-2.20 (m, 1H),1.93 (s, 1H), 1.62-1.74 (m, 1H).

Step 2 methyl6-chloro-5-[4-(1-hydroxycyclobutyl)-3-methylphenyl]-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(81 mg, 0.25 mmol), 1-(4-bromo-2-methylphenyl)cyclobutanol (61 mg, 0.25mmol), 4 M aqueous potassium carbonate (0.51 mL, 1 mmol), toluene (3mL), and ethanol (1 mL) was sparged with nitrogen for 10 minutes, thentreated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (10 mg, 0.012 mmol). The reaction mixture wasplaced in a pre-heated oil bath at 105° C. and stirred. After 2 hoursthe reaction was cooled to room temperature, diluted with ethyl acetate,washed with water and saturated brine, dried over magnesium sulfate,filtered and concentrated in vacuo to afford 113 mg brown foam. The foamwas dissolved in chloroform and a precipitate formed, which wascollected by filtration to afford the title compound as a beige solid(44 mg, 47% yield).

MS (ES−) 368.2 (M−H)⁻. ¹H NMR (500 MHz, CD₃OD) δ 8.00 (s, 1H), 7.97 (s,1H), 7.58 (s, 1H), 7.40 (d, J=7.56 Hz, 1H), 7.19-7.27 (m, 2H), 3.87 (s,3H), 2.69-2.79 (m, 2H), 2.39-2.51 (m, 5H), 2.11-2.23 (m, 1H), 1.69-1.81(m, 1H).

Step 36-chloro-5-[4-(1-hydroxycyclobutyl)-3-methylphenyl]-1H-indole-3-carboxylicacid

Methyl6-chloro-5-[4-(1-hydroxycyclobutyl)-3-methylphenyl]-1H-indole-3-carboxylate(44 mg, 0.12 mmol) was dissolved in methanol (3 mL) and 1 N aqueoussodium hydroxide (1 mL, 1 mmol), and the mixture was stirred at 75° C.for 41 hours. The mixture was cooled to room temperature and treatedwith Aldrich Amberjet 1200H acidic resin (˜1 g), then stirred for 5minutes until a pH of 3 was obtained. The resin was filtered and washedwith methanol and the filtrate was concentrated in vacuo to afford 39 mgcolorless solid, which was purified by reversed-phase HPLC to afford thetitle compound (36.6 mg, 58% yield). MS (ES−) 354.265 (M−H)⁻. retentiontime=2.79 min; Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Modifier:TFA 0.05%; Gradient: 95% H₂O/5% MeCN linear to 5% H₂O/95% MeCN over 4.0min, HOLD at 5% H₂O/95% MeCN to 5.0 min; Flow: 2.0 mL/min

Example 426-chloro-5-[3-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylicacid

Step 1 1-(4-bromo-2-fluorophenyl)cyclobutanol

To a solution of 4-bromo-2-fluoro-1-iodobenzene (500 mg, 1.66 mmol) intetrahydrofuran (5 mL) at −78° C. was added n-butyl lithium (2.5 M inhexane, 0.8 mL, 0.8 mmol) dropwise over 15 minutes. The reaction mixturewas stirred at −78° C. for 30 minutes, treated with neat cyclobutanone(0.12 mL, 1.66 mmol) dropwise over 10 minutes, and stirred at −78° C.for an additional 1.5 hours. The reaction was quenched with saturatedaqueous NH₄Cl, warmed to room temperature and extracted with ethylacetate (2×). The combined organic layers were dried over magnesiumsulfate, filtered and concentrated in vacuo to afford 300 mg yellow oil,which was purified by silica gel chromatography (12 g silica, 0-50%ethyl acetate/heptane, 21 column volumes). Product fractions werecombined and concentrated in vacuo to afford the title compound as acolorless oil (215 mg, 53% yield). GCMS 244/246. (m/z)¹H NMR (500 MHz,CDCl₃) δ 7.20-7.31 (m, 3H), 2.56-2.66 (m, 2H), 2.40-2.55 (m, 1H),2.31-2.40 (m, 2H), 2.14 (m, 1H), 1.75 (m, 1H).

Step 2 methyl6-chloro-5-[3-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(75 mg, 0.23 mmol), 1-(4-bromo-2-fluorophenyl)cyclobutanol (57 mg, 0.23mmol), 4 M aqueous potassium carbonate (0.47 mL, 0.9 mmol), toluene (3mL), and ethanol (1 mL) was sparged with nitrogen for 10 minutes, thentreated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (9 mg, 0.011 mmol). The reaction mixture wasplaced in a pre-heated oil bath at 105° C. and stirred for 2 hours. Thereaction was cooled to room temperature, diluted with ethyl acetate,washed with water and saturated brine (lx each), dried over magnesiumsulfate, filtered and concentrated in vacuo to afford a brownsemi-solid, which was purified by flash chromatography (12 g silica,10-50% ethyl acetate/heptane, 21 column volumes). The product fractionswere combined and concentrated in vacuo to afford the title compound asa colorless solid (49 mg, 56% yield). MS (ES−) 372.2 (M−H)⁻. ¹H NMR (400MHz, CDCl₃) δ 8.59 (s, 1H), 8.10 (s, 1H), 7.94 (d, J=2.93 Hz, 1H), 7.54(s, 1H), 7.38-7.44 (m, 1H), 7.18-7.28 (m, 2H), 3.89 (s, 3H), 2.66-2.77(m, 2H), 2.42 (m, 2H), 2.11-2.22 (m, 1H), 1.74-1.86 (m, 1H).

Step 36-chloro-5-[3-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylicacid

Methyl6-chloro-5-[3-fluoro-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylate(49 mg, 0.13 mmol) was dissolved in MeOH (3 mL) and 1 N NaOH (1 mL, 1mmol), and the mixture was stirred at 75° C. for 41 hours. The mixturewas cooled to room temperature and treated with Aldrich Amberjet 1200Hacidic resin (˜1 g), then stirred for 5 minutes until a pH of 3 wasobtained. The resin was filtered and washed with methanol and thefiltrate was concentrated in vacuo to afford 50 mg colorless solid,which was purified by reversed-phase HPLC to afford the title compound(37 mg, 58% yield). MS (ES−) 358.1 (M−H)⁻; retention time=2.71 min;Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Modifier: TFA 0.05%;Gradient: 95% H₂O/5% MeCN linear to 5% H₂O/95% MeCN over 4.0 min, HOLDat 5% H₂O/95% MeCN to 5.0 min; Flow: 2.0 mL/min.

Example 43 5-(biphenyl-4-yl)-6-chloro-1H-indole-3-carboxylic acid

Step 1 methyl 5-(biphenyl-4-yl)-6-chloro-1H-indole-3-carboxylate

A mixture of methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (150 mg,0.52 mmol), 4-biphenylboronic acid (113 mg, 0.57 mmol) and 2M aqueouspotassium carbonate (2M, 1.04 mL, 2.08 mmol) in toluene (3.0 mL) andethanol (1.0 mL) was degassed with nitrogen for 10 minutes. The reactionmixture was then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20.0 mg,0.026 mmol) and heated at 110° C. for 2 h in a sealed reaction vessel,which caused the reaction to appear burnt orange. The reaction mixturewas cooled to room temperature and poured into ethyl acetate and water.The layers were separated and the aqueous layer was back-extracted withethyl acetate. The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated in vacuo. The materialwas then dissolved in ethyl acetate and methanol then silica gel wasadded. The solvent was removed and the crude material adsorbed ontosilica gel was added to a column of silica gel and eluted with ethylacetate/heptanes (1:4 to 1:1) to give the desired product as a tan solid61 mg (35% yield). MS (ES+) 362.5 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.53(br. s., 1H), 8.17 (s, 1H), 7.94 (d, J=2.15 Hz, 1H), 7.61-7.72 (m, 4H),7.57 (d, J=6.05 Hz, 2H), 7.45 (t, J=7.61 Hz, 2H), 7.31-7.40 (m, 1H),3.89 (s, 3H).

Step 2 5-(biphenyl-4-yl)-6-chloro-1H-indole-3-carboxylic acid

A solution of methyl 5-(biphenyl-4-yl)-6-chloro-1H-indole-3-carboxylate(50 mg, 0.14 mmol) in methanol (1.5 mL) and sodium hydroxide (1 M, 0.50mmol, 0.50 mL) was stirred at 75° C. for 24 hours. The cooled reactionmixture was neutralized to an acidic pH with 1M HCl and extracted twicewith ethyl acetate. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. Methylene chloride wasthen added and solid precipitated. The slurry was stirred for 30 minutesthen filtered and washed with methylene chloride and a small amount ofethyl acetate. The solids were dried in vacuo to provide the desiredproduct as a tan solid (17 mg, 35% yield). MS (ES+) 348.1 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 12.14 (br. s., 1H), 11.98 (br. s., 1H), 8.10 (d,J=2.93 Hz, 1H), 8.01 (s, 1H), 7.75 (t, J=8.42 Hz, 4H), 7.67 (s, 1H),7.54 (d, J=8.05 Hz, 2H), 7.50 (t, J=7.56 Hz, 2H), 7.32-7.45 (m, 1H).

Example 44 6-chloro-5-(2-fluoro-4-methoxyphenyl)-1H-indole-3-carboxylicacid

Step 1 methyl6-chloro-5-(2-fluoro-4-methoxyphenyl)-1H-indole-3-carboxylate

A mixture of methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (150 mg,0.52 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (93 mg, 0.55 mmol)and aqueous 2M potassium carbonate (2M, 1.04 mL, 2.08 mmol) in toluene(3.0 mL) and ethanol (1.0 mL) was degassed with nitrogen for 10 minutesthen treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20.0 mg,0.026 mmol). The reaction mixture was then heated at 110° C. for 2 h ina sealed reaction vessel, which caused the reaction mixture to appearburnt orange. The cooled reaction mixture was poured into ethyl acetateand water. The layers were separated and the aqueous layer wasback-extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentratedin vacuo. The material was then dissolved in ethyl acetate and methanolthen silica gel was added. The solvent was removed and the crudematerial adsorbed onto silica gel was added to a column of silica geland eluted with ethyl acetate/heptane (1:4 to 1:1) to provide thedesired product (55 mg, 32% yield) as a tan solid. MS (ES+) 334.5(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (br. s., 1H), 8.15 (s, 1H),7.86 (s, 1H), 7.63 (s, 1H), 7.26 (t, J=8.69 Hz, 1H), 6.90 (dd, J=11.91,2.15 Hz, 1H), 6.85 (dd, J=8.49, 2.24 Hz, 1H), 3.80 (s, 3H), 3.76 (s,3H).

Step 2 6-chloro-5-(2-fluoro-4-methoxyphenyl)-1H-indole-3-carboxylic acid

A mixture of methyl6-chloro-5-(2-fluoro-4-methoxyphenyl)-1H-indole-3-carboxylate (50 mg,0.15 mmol) in methanol (1.5 mL) and aqueous 1M sodium hydroxide (1 M,0.50 mmol, 0.50 mL) was heated at 75° C. for 24 hours. The reaction wasthen acidified with 1M HCl to pH=2 and diluted with ethyl acetate. Thelayers were separated and the aqueous layer was back-extracted twicewith ethyl acetate. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo to provide a crude solid. Asmall amount of methylene chloride was added and the crude materialslurried for 5 minutes. The solid was then filtered and washed withethyl acetate to provide the title compound (13 mg, 27% yield).

MS (ES+) 320.0 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.12 (br. s., 1H),11.98 (br. s., 1H), 8.09 (d, J=2.68 Hz, 1H), 7.91 (s, 1H), 7.64 (s, 1H),7.29 (t, J=8.54 Hz, 1H), 6.93 (dd, J=11.95, 1.95 Hz, 1H), 6.88 (dd,J=8.42, 2.07 Hz, 1H), 3.83 (s, 3H).

Example 456-chloro-5-{4-[1-(methylsulfonyl)azetidin-2-yl]phenyl}-1H-indole-3-carboxylicacid

Step 1 2-(4-bromophenyl)-1-(methylsulfonyl)azetidine

To a mixture of 2-(4-bromophenyl)azetidine (200 mg, 0.808 mmol) andtriethylamine (98 mg, 0.97 mmol) in anhydrous dichloromethane (6 mL) wasadded methanesulfonyl chloride (111 mg, 0.97 mmol). The mixture wasstirred at rt for 5 hours. The mixture was poured into ethyl acetate andwashed with water. The organic phase was dried over sodium sulfate,filtered, concentrated in vacuo to give the title compound (200 mg, 85%yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ7.50 (d, 2H), 7.25 (d,2H), 5.30-5.20 (m, 1H), 420-4.00 (m, 2H), 3.63 (s, 3H), 2.70 (m, 1H),2.15 (m, 1H).

Step 2 methyl6-chloro-5-{4-[1-(methylsulfonyl)azetidin-2-yl]phenyl}-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(100 mg, 0.311 mmol), 2-(4-bromophenyl)-1-(methylsulfonyl)azetidine(108.2 mg, 0.373 mmol), 2.0 M potassium carbonate solution (0.5 mL, 1.0mmol), and Pd(dppf)Cl₂ (30 mg, 0.03 mmol) in toluene/ethanol (1.44mL/0.48 mL) was stirred at 110° C. for 2.5 hours. TLC (petroleumether/ethyl acetate=3:1) showed that the reaction was complete. Themixture was poured into ethyl acetate and washed with water. The organicphase was dried over sodium sulfate, filtered, and concentrated to givea residue, which was purified by prep-TLC to give the title compound (80mg, 62% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ12.30-12.10 (s, 1H), 8.2 (s, 1H), 7.92 (s, 1H), 7.65 (s, 1H), 7.55 (d,2H), 7.45 (d, 2H), 5.35 (m, 1H), 4.32 (m, 1H), 4.0 (m, 1H), 3.75 (s,3H), 3.15 (m, 2H), 3.05 (s, 3H).

Step 36-chloro-5-{4-[1-(methylsulfonyl)azetidin-2-yl]phenyl}-1H-indole-3-carboxylicacid

To a solution of methyl6-chloro-5-{4-[1-(methylsulfonyl)azetidin-2-yl]phenyl}-1H-indole-3-carboxylate(80 mg, 0.22 mmol) in methanol (8 mL) was added 1.0 M aq. NaOH (2.0 mL,2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixturewas adjusted to pH 7 and purified by prep-HPLC to give the titlecompound (20 mg, 13% yield) as a white solid. MS (ES+) 445.0 (M+CH₃CN)⁺.¹H NMR (400 MHz, DMSO-d₆): δ 8.05 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H),7.50-7.30 (m, 4H), 4.70 (m, 1H), 3.10 (m, 2H), 2.89 (s, 3H), 1.90-1.80(m, 2H).

Example 465-[4-(1-acetylazetidin-2-yl)phenyl]-6-chloro-1H-indole-3-carboxylic acid

Step 1 1-[2-(4-bromophenyl)azetidin-1-yl]ethanone

To a mixture of 2-(4-bromophenyl)azetidine (200 mg, 0.808 mmol) andtriethylamine (98 mg, 0.97 mmol) in anhydrous dichloromethane (6 mL) wasadded acetic anhydride (200 mg, 0.97 mmol). The mixture was stirred atrt for 5 hours. The mixture was poured into ethyl acetate and washedwith water. The organic phase was dried over sodium sulfate, filtered,and concentrated in vacuo to give the title compound (100 mg, 49% yield)as a yellow oil that was taken on without further purification.

Step 2 methyl5-[4-(1-acetylazetidin-2-yl)phenyl]-6-chloro-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(100 mg, 0.311 mmol), 1-[2-(4-bromophenyl)azetidin-1-yl]ethanone (100mg, 0.373 mmol), 2.0 M aqueous potassium carbonate (0.50 mL, 1.0 mmol),and Pd(dppf)Cl₂ (30 mg, 0.03 mmol) in toluene/ethanol (1.44 mL/0.48 mL)was stirred at 110° C. for 2.5 hours. The mixture was poured into ethylacetate and washed with water. The organic phase was dried over sodiumsulfate, filtered, and concentrated to give a residue. This was purifiedby preparative TLC to give the title compound (40 mg, 51% yield) as awhite solid.

Step 35-[4-(1-acetylazetidin-2-yl)phenyl]-6-chloro-1H-indole-3-carboxylic acid

To a solution of methyl5-[4-(1-acetylazetidin-2-yl)phenyl]-6-chloro-1H-indole-3-carboxylate (40mg, 0.11 mmol) in methanol (8 mL) was added 1.0 M aq. NaOH (2.0 mL, 2.0mmol). The mixture was stirred at 70° C. for 24 hours. The mixture wasadjusted to pH 7 and purified by reverse phase HPLC to give the titlecompound (3 mg, 7% yield) as a white solid.

MS (ES+) 369.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.05 (s, 1H), 7.95 (s,1H), 7.60 (s, 1H), 7.40 (m, 4H), 4.80-4.70 (m, 3H), 2.00-1.90 (m, 2H),1.93 (s, 3H).

Example 476-chloro-5-{4[(2S)-pyrrolidin-2-ylmethoxy]phenyl}-1H-indole-3-carboxylicacid

Step 1 methyl6-chloro-5-{4[(2S)-pyrrolidin-2-ylmethoxy]phenyl}-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(80 mg, 0.146 mmol), (S)-2-((4-bromophenoxy)methyl)pyrrolidine (77 mg,0.3 mmol), 2.0 M aqueous potassium carbonate (0.5 mL, 1.0 mmol), andPd(dppf)Cl₂ (10 mg, 0.01 mmol) in toluene/ethanol (1.44 mL/0.48 mL) wasstirred at 110° C. for 2.5 hours. The mixture was poured into ethylacetate and washed with water. The organic phase was dried over sodiumsulfate, filtered, and concentrated to give a residue, which waspurified by preparative TLC to give the title compound (40 mg, 42%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.92 (s, 1H), 7.80(s, 1H), 7.55 (s, 1H), 7.45 (d, 2H), 6.85 (d, 2H), 4.10 (m, 1H), 3.75(s, 3H), 3.65 (m, 1H), 3.52 (m, 1H), 3.05 (m, 2H), 2.05 (m, 1H), 1.90(m, 2H), 1.70 (m, 1H).

Step 26-chloro-5-{4[(2S)-pyrrolidin-2-ylmethoxy]phenyl}-1H-indole-3-carboxylicacid

To a solution of methyl6-chloro-5-{4-[(2S)-pyrrolidin-2-ylmethoxy]phenyl}-1H-indole-3-carboxylate(40 mg, 0.22 mmol) in methanol (8 mL) was added 1.0 M aqueous NaOH (2.0mL, 2.0 mL). The mixture was stirred at 70° C. for 24 hours. The mixturewas adjusted to pH 7 and purified by reverse phase HPLC to give thetitle compound (10 mg, 11% yield) as a white solid.

MS (ES+) 371.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ12.00 (S, 1H), 8.35(s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.60 (s, 1H), 7.35 (m, 2H), 7.0 (m,2H), 4.05 (m, 2H), 3.70 (m, 1H), 3.05 (m, 2H), 2.01 (m, 1H), 1.8 (m,2H), 1.62 (m, 1H).

Example 486-chloro-5-{4-[2-(piperazin-1-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid

Step 1 methyl6-chloro-5-{4-[2-(piperazin-1-yl)ethoxy]phenyl}-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(80 mg, 0.15 mmol), 1-(2-(4-bromophenoxy)ethyl)piperazine (86 mg, 0.30mmol), 2.0 M aqueous potassium carbonate (0.50 mL, 1.0 mmol), andPd(dppf)Cl₂ (10 mg, 0.01 mmol) in toluene/ethanol (1.44 mL/0.48 mL) wasstirred at 110° C. for 2.5 hours. The mixture was poured into ethylacetate and washed with water. The organic phase was dried over sodiumsulfate, filtered, and concentrated in vacuo to give a residue, whichwas purified by preparative TLC to give the title compound (40 mg, 40%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ8.50 (s, 1H), 8.10(s, 1H), 7.98 (s, 1H), 7.55 (m, 1H), 7.45 (m, 2H), 7.00 (m, 2H), 4.20(m, 2H), 3.90 (s, 3H), 2.99 (m, 4H), 2.85 (m, 2H), 2.60 (m, 4H).

Step 26-chloro-5-{4-[2-(piperazin-1-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid

To a solution of compound methyl6-chloro-5-{4-[2-(piperazin-1-yl)ethoxy]phenyl}-1H-indole-3-carboxylate(80 mg, 0.22 mmol) in methanol (8 mL) was added aq. NaOH (2 mL, 1.0 N).The mixture was stirred at 70° C. for 24 hours. The mixture was adjustedto pH 7 and purified by reverse phase HPLC to give the title compound(10 mg, 11% yield) as a white solid. MS (ES+) 400.2 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆): δ 12.00 (S, 1H), 8.35 (s, 1H), 8.05 (s, 1H), 7.95 (s,1H), 7.60 (s, 1H), 7.35 (d, 2H), 7.00 (m, 2H), 4.10 (m, 2H), 2.90 (m,4H), 2.70 (m, 2H), 2.60 (m, 4H).

Example 506-chloro-5-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-1H-indole-3-carboxylicacid

Step 1 methyl6-chloro-5-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(80 mg, 0.15 mmol), (1S,2S)-2-(4-bromophenoxy)cyclohexanol (81 mg, 0.30mmol), 2.0 M aqueous potassium carbonate (0.50 mL, 1.0 mmol), andPd(dppf)Cl₂ (10 mg, 0.01 mmol) in toluene/ethanol (1.44 mL/0.48 mL) wasstirred at 110° C. for 2.5 hours. The mixture was poured into ethylacetate and washed with water. The organic phase was dried over sodiumsulfate, filtered, and concentrated to give a residue, which waspurified by preparative TLC to give the title compound (80 mg, 90%yield) as a white solid.

Step 26-chloro-5-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-1H-indole-3-carboxylicacid

To a solution of methyl6-chloro-5-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-1H-indole-3-carboxylate(80 mg, 0.22 mmol) in methanol (8 mL) was added aq. 1.0M NaOH (2.0 mL,2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixturewas adjusted to pH 7 and purified by reverse phase HPLC to give thetitle compound (12.6 mg, 16% yield) as a white solid. MS (ES+) 408.2(M+Na)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 12.40-11.90 (br. s, 1H), 11.85 (s,1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.61 (m, 1H), 7.32 (d, 2H), 7.00 (d,2H), 4.93 (m, 1H), 4.10 (m, 1H), 3.57 (m, 1H), 2.05 (m, 1H), 1.88 (m,1H), 1.53 (m, 2H), 1.40-1.10 (m, 4H).

Example 51 6-chloro-5-(4-methylphenyl)-1H-indole-3-carboxylic acid

Step 1 methyl 6-chloro-5-(4-methylphenyl)-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(80 mg, 0.15 mmol), 4-bromotoluene (56 mg, 0.30 mmol), 2.0 M aqueouspotassium carbonate (0.5 mL, 1.0 mmol), and Pd(dppf)Cl₂ (10 mg, 0.01mmol) in toluene/ethanol (1.44 mL/0.48 mL) was stirred at 110° C. for2.5 hours. The mixture was poured into ethyl acetate and washed withwater. The organic phase was dried over sodium sulfate, filtered, andconcentrated to give a residue, which was purified by preparative TLC togive the title compound (80 mg, 100% yield) as a white solid. ¹H NMR(400 MHz, CDCl₃): δ 8.51 (br. s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.55(s, 1H), 7.42 (d, 2H), 7.25 (d, 2H), 3.90 (s, 3H), 2.42 (s, 3H).

Step 2 6-chloro-5-(4-methylphenyl)-1H-indole-3-carboxylic acid

To a solution of methyl6-chloro-5-(4-methylphenyl)-1H-indole-3-carboxylate (80 mg, 0.22 mmol)in methanol (8 mL) was added 1.0M aqueous NaOH (2.0 mL, 2.0 mmol). Themixture was stirred at 70° C. for 24 hours. The mixture was adjusted topH 7 and purified by reverse phase HPLC to give the title compound (10mg, 13% yield) as a white solid. MS (ES+) 286.1 (M+H)⁺. ¹H NMR (400 MHz,DMSO): 612.20-11.95 (br. s, 1H), 11.90 (br. s, H), 8.10 (s, 1H), 7.95(s, 1H), 7.65 (s, 1H), 7.35-7.20 (m, 4H), 2.35 (s, 3H).

Example 526-chloro-5-{4-[3-(piperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylicacid

Step 1 tert-butyl 4-(3-(4-bromophenoxy)propyl)piperazine-1-carboxylate

To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol)and tert-butyl piperazine-1-carboxylate (144 mg, 1.02 mmol) inacetonitrile (6.0 mL) was added Cs₂CO₃ (365 mg, 1.10 mmol). The mixturewas stirred at 75° C. for 5 hours. The mixture was poured into ethylacetate and washed with water. The organic phase was dried over sodiumsulfate, filtered, and concentrated to give the title compound (300 mg,75% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.40 (d, 2H),6.75 (d, 2H), 3.95 (m, 2H), 3.42 (m, 4H), 2.54 (t, 2H), 2.40 (m, 4H),2.01-1.89 (m, 2H), 1.50-1.40 (s, 9H).

Step 2 1-(3-(4-bromophenoxy)propyl)piperazine

To a mixture of tert-butyl4-(3-(4-bromophenoxy)propyl)piperazine-1-carboxylate (200 mg, 0.50 mmol)in ethyl acetate (10 mL) was added HCl/ethyl acetate (20 mL). Themixture was stirred at rt for 4 hours. The mixture was concentrated togive the title compound (150 mg, 100% yield) as a white solid.

Step 3 methyl6-chloro-5-{4-[3-(piperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylate

A mixture of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(100 mg, 0.311 mmol), 1-(3-(4-bromophenoxy)propyl)piperazine (149 mg,0.373 mmol), 2.0 M aqueous potassium carbonate (0.5 mL, 1.0 mmol), andPd(dppf)Cl₂ (30 mg, 0.03 mmol) in toluene/ethanol (1.44 mL/0.48 mL) wasstirred at 110° C. for 2.5 hours. The mixture was poured into ethylacetate and washed with water. The organic phase was dried over sodiumsulfate, filtered, and concentrated to give a residue, which waspurified by preparative TLC to give the title compound (90 mg, 70%yield) as a white solid.

Step 46-chloro-5-{4-[3-(piperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylicacid

To a solution of methyl6-chloro-5-{4-[3-(piperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylate(90 mg, 0.22 mmol) in methanol (8 mL) was added 1.0 M aqueous NaOH (2.0mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. Themixture was adjusted to pH 7 and purified by reverse phase HPLC to givethe title compound (42 mg, 47% yield) as a white solid.

MS (ES+) 414.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ7.30 (s, 1H), 7.05(s, 1H), 6.70 (s, 1H), 6.55 (d, 2H), 6.15 (d, 2H), 3.80 (m, 2H), 3.30(m, 2H), 2.30 (m, 4H), 1.85 (m, 4H), 1.20 (m, 2H).

Example 536-chloro-5-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylicacid

Step 1 1-(3-(4-bromophenoxy)propyl)-4-methylpiperazine

To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol)and 1-methylpiperazine (100 mg, 1.02 mmol) in CH₃CN (6 mL) was addedCs₂CO₃ (365 mg, 1.10 mmol). The mixture was stirred at 75° C. for 5hours. The mixture was poured into ethyl acetate and washed with water.The organic phase was dried over sodium sulfate, filtered, andconcentrated to give the title compound (280 mg, 75% yield) as a yellowoil.

¹H NMR (400 MHz, DMSO-d₆): δ 7.32 (d, 2H), 6.80 (d, 2H), 3.88 (m, 2H),2.51-2.09 (m, 10H), 2.05 (s, 3H), 1.75 (m, 2H).

Step 2 methyl6-chloro-5-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylate

A mixture of of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(100 mg, 0.311 mmol), 1-(3-(4-bromophenoxy)propyl)-4-methylpiperazine(130 mg, 0.373 mmol), 2.0 M aqueous potassium carbonate (0.50 mL, 1.0mmol), and Pd(dppf)Cl₂ (30 mg, 0.03 mmol) in toluene/ethanol (1.44mL/0.48 mL) was stirred at 110° C. for 2.5 hours. The mixture was pouredinto ethyl acetate and washed with water. The organic phase was driedover sodium sulfate, filtered, and concentrated to give a residue, whichwas purified by preparative TLC to give the title compound (80 mg, 75%yield) as a white solid.

Step 36-chloro-5-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylicacid

To a solution of methyl6-chloro-5-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylate(80 mg, 0.22 mmol) in methanol (8 mL) was added 1.0 M aqueous NaOH (2.0mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. Themixture was adjusted to pH 7 and purified by reverse phase HPLC to givethe title compound (25 mg, 28% yield) as a white solid. MS (ES+) 428.1(M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.41 (br. s, 1H), 8.03 (s, 1H), 7.97(s, 1H), 7.56 (s, 1H), 7.34 (d, 2H), 6.98 (d, 2H), 4.12 (t, 2H),3.20-2.75 (m, 10H), 2.70 (s, 3H), 2.10-2.01 (m, 2H).

Example 546-chloro-5-{4-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylicacid

Step 1 4-(3-(4-bromophenoxy)propyl)morpholin-3-one

To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol)and morpholin-3-one (100 mg, 1.02 mmol) in DMF (6 mL) was added NaH (365mg, 1.10 mmol). The mixture was stirred at 75° C. for 5 hours. Themixture was poured into ethyl acetate and washed with water. The organicphase was dried over sodium sulfate, filtered, and concentrated to givethe title compound (100 mg, 35%) as a yellow oil.

Step 2 methyl6-chloro-5-{4-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylate

A mixture of of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(100 mg, 0.311 mmol), 4-(3-(4-bromophenoxy)propyl)morpholin-3-one (100mg, 0.373 mmol), 2 N potassium carbonate (0.5 mL, 2 mmol), andPd(dppf)Cl₂ (30 mg, 0.03 mmol) in toluene/ethanol (1.44 mL/0.48 mL) wasstirred at 110° C. for 2.5 hours. The mixture was poured into ethylacetate and washed with water. The organic phase was dried over sodiumsulfate, filtered, and concentrated to give a residue, which waspurified by preparative TLC to give the title compound (50 mg, 50%yield) as a white solid.

Step 36-chloro-5-{4-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylicacid

To a solution of methyl6-chloro-5-{4-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylate(55 mg, 0.22 mmol) in methanol (8 mL) was added 1.0 M aq. NaOH (2.0 mL,2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixturewas adjusted to pH 7 and purified by reverse phase HPLC to give thetitle compound as a white solid (5 mg, 9% yield). MS (ES+) 429.1 (M+H)⁺.¹H NMR (400 MHz, CD₃OD): δ 7.90 (m, 2H), 7.5 (s, 1H), 7.29 (d, 2H), 6.92(d, 2H), 4.05 (m, 4H), 3.83 (t, 2H), 3.58 (t, 2H), 3.42 (t, 2H), 2.05(m, 2H).

Example 55(S)-6-Chloro-5-(3-methoxy-4-(pyrrolidin-2-ylmethoxy)phenyl)-1H-indole-3-carboxylicacid

Step 1 (S)-tert-butyl2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

To a solution of (S)-tert-butyl2-(hydroxymethyl)pyrrolidine-1-carboxylate (201 mg, 1.00 mmol) andtriethylamine (0.21 mL, 1.5 mmol) in tert-butyl methyl ether (4 mL) wasadded methanesulfonyl chloride (0.095 mL, 1.2 mmol). After 90 min., themixture was filtered, washing the white solid with tert-butyl methylether (3×2 mL). The filtrate was concentrated in vacuo to provide thetitle compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃,): δ 4.40-3.95(m, 3H), 3.49-3.32 (m, 2H), 3.02 (s, 3H), 2.11-1.80 (m, 4H), 1.48 (s,9H).

Step 2 (S)-tert-butyl2-((4-bromo-2-methoxyphenoxy)methyl)pyrrolidine-1-carboxylate

To a solution of (S)-tert-butyl2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (279 mg, 1.00mmol) and 4-bromo-2-methoxyphenol (325 mg, 1.57 mmol) inN,N-dimethylformamide (5.55 mL) was added cesium carbonate (651 mg, 2.00mmol). The mixture was heated to 100° C. After 22 h, the mixture wasallowed to cool to 23° C. and diluted with water (30 mL). The mixturewas extracted with ethyl acetate (3×30 mL). The combined organics weredried over sodium sulfate and filtered. The filtrate was concentrated invacuo. Purification by column chromatography (silica gel, 0-50% ethylacetate in dichloromethane) afforded the title compound as an amber oil.MS (ES+) 408.2 (M+Na)⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.07-6.79 (m, 3H),4.25-4.10 (m, 2H), 4.01-3.73 (m, 1H), 3.84 (s, 3H), 3.48-3.26 (m, 2H),2.16-1.80 (m, 4H), 1.48 (s, 9H).

Step 3 (S)-methyl5-(4-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-3-methoxyphenyl)-6-chloro-1H-indole-3-carboxylate

To a solution of (S)-tert-butyl2-((4-bromo-2-methoxyphenoxy)methyl)pyrrolidine-1-carboxylate (77 mg,0.20 mmol) in toluene (1.5 mL) was added methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(77 mg, 0.24 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (6.7 mg, 0.0080 mmol), ethanol (absolute, 0.5mL), and potassium carbonate (2 M solution in water, 0.4 mL, 0.80 mmol).Nitrogen was bubbled through the mixture for 20 min. The mixture wasthen sealed and heated to 90° C. After 18 h, the mixture was allowed tocool to 23° C., diluted with ethyl acetate (5 mL), and filtered throughCelite. The filtrate was dried over sodium sulfate and concentrated invacuo. Purification by column chromatography (silica gel, 0-50% ethylacetate in heptane) afforded the title compound contaminated withneopentyl glycol.

MS (ES+) 515.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.60 (br. s, 1H), 8.14(br. s, 1H), 7.95 (d, 1H), 7.55 (s, 1H), 7.17-6.97 (m, 3H), 4.35-4.20(m, 2H), 4.10-3.81 (m, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.50-3.28 (m,2H), 2.24-1.83 (m, 4H), 1.51 (br. s, 9H).

Step 4 (S)-methyl6-chloro-5-(3-methoxy-4-(pyrrolidin-2-ylmethoxy)phenyl)-1H-indole-3-carboxylate

To a solution of (S)-methyl5-(4-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-3-methoxyphenyl)-6-chloro-1H-indole-3-carboxylate(25.8 mg, 0.050 mmol) in dichloromethane (0.5 mL) was added hydrogenchloride (4 M solution in dioxane, 0.075 mL, 0.30 mmol). After 2 h, thesolution was concentrated in vacuo to provide the title compound as thehydrochloride salt contaminated with neopentyl glycol. MS (ES+) 415.2(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.80 (br. s, 1H), 8.17 (d, 1H),7.94 (s, 1H), 7.65 (s, 1H), 7.11 (d, 1H), 7.06 (d, 1H), 6.96 (dd, 1H),4.34-4.26 (m, 2H), 4.15 (dd, 1H), 4.01-3.92 (m, 1H), 3.82 (s, 3H), 3.79(s, 3H), 3.29-3.19 (m, 2H), 2.21-2.10 (m, 1H), 2.08-1.86 (m, 2H),1.83-1.72 (m, 1H).

Step 5(S)-6-chloro-5-(3-methoxy-4-(pyrrolidin-2-ylmethoxy)phenyl)-1H-indole-3-carboxylicacid

To a solution of (S)-methyl6-chloro-5-(3-methoxy-4-(pyrrolidin-2-ylmethoxy)phenyl)-1H-indole-3-carboxylatehydrochloride (22.6 mg, 0.050 mmol) in methanol (0.26 mL) was addedtetrahydrofuran (0.26 mL) and sodium hydroxide (1 N in water, 0.26 mL,0.26 mmol). The mixture was then sealed and heated to 65° C. After 41 h,the mixture was allowed to cool to 23° C., concentrated in vacuo,diluted with water (1 mL), then acidified to pH 7.5 with hydrochloricacid (1 N in water). The solid was filtered and purified by reversephase HPLC to provide the title compound. MS (ES+) 401.2 (M+H)⁺. HPLCretention time: 1.44 min, Waters XBridge C18, 5 μm, 4.6×50 mm, 0.03%NH₄OH, 5-95% acetonitrile in water gradient over 4.0 min, hold at 95%acetonitrile in water to 5.0 min, flow 2.0 mL/min.

Example 566-chloro-5-(4-(2-hydroxypropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylicacid

Step 1 2-(4-bromo-2-methoxyphenyl)propan-2-ol

To a solution of 5-bromo-2-iodoanisole (668 mg, 2.14 mmol) and acetone(0.471 mL, 6.40 mmol) in tetrahydrofuran (7.62 mL) at −78° C. was addedn-BuLi (2.5M in hexane, 0.940 mL, 2.35 mmol) in a dropwise manner. Thereaction mixture was stirred at −78° C. for 2 hours. The reactionmixture was quenched with saturated aqueous ammonium chloride, warmed toroom temperature and extracted with ethyl acetate (2×). The combinedorganic layers were dried over magnesium sulfate and filtered, andconcentrated under reduced pressure yielding 680 mg of crude oil.Purification by column chromatography (0-10% ethyl acetate/heptanes)afforded the title compound (133 mg, 25% yield) as a clear, colorlessoil. MS (ES+) 226.9 (M−H₂O+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ: 7.20 (d, 1H),7.06-7.10 (m, 1H), 7.04 (d, 1H), 3.91 (s, 3H), 1.58 (s, 6H).

Step 2 methyl6-chloro-5-(4-(2-hydroxypropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylate

To a solution of 2-(4-bromo-2-methoxyphenyl)propan-2-ol (50.0 mg, 0.20mmol) in toluene (0.81 mL) was added methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(72 mg, 0.22 mmol), ethanol (0.43 mL), and tetrahydrofuran (0.43 mL).This was followed by the addition of 2M potassium carbonate aqueous(0.58 mL, 1.2 mmol). The reaction was evacuated and back filled withnitrogen (3×) then Pd(dppf)Cl₂ (19.0 mg, 0.023 mmol) was added and thereaction heated to 115° C. for 3 hours. The reaction was then cooled toroom temperature and filtered through a pad of celite washing with ethylacetate. The filtrate was concentrated under reduced pressure andpurified via column chromatography (0-40% ethyl acetate/heptanes) toprovide the title compound (45 mg, 59% yield) as a solid.

MS (ES+) 356.1 (M−H₂O+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ: 8.52 (s, 1H), 8.14(s, 1H), 7.95 (d, 1H), 7.56 (s, 1H), 7.37 (d, 1H), 7.04-7.09 (m, 2H),4.23 (s, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 1.67 (s, 6H).

Step 36-chloro-5-(4-(2-hydroxypropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylicacid

To a flask containing methyl6-chloro-5-(4-(2-hydroxypropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylate(24.0 mg, 0.064 mmol) was added methanol (0.64 mL), and 1N NaOH (0.19mL, 0.19 mmol). The reaction was heated at 70° C. for 18 h. The reactionwas then concentrated to remove most of the methanol and then dissolvedin water. 0.19 mL of 1 N HCl was then added to the mixture to pH 2.Solid precipitated out. The solid was collected with a Buchner funneland washed with water to provide crude6-chloro-5-(4-(2-hydroxypropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylicacid. The crude material was purified by reverse phase chromatography togive the title compound. MS (ES⁻) 358.1 (M−H)⁻: Retention time: 1.40min. Column: Waters XBridge dC18 4.6×50 mm, 5 μm. Modifier: NH₄OH 0.03%.Gradient: 95% H₂O/5% MeCN linear to 5% H₂O/95% MeCN over 4.0 min, HOLDat 5% H₂O/95% MeCN to 5.0 min. Flow: 2.0 mL/min.

Example 576-chloro-5-(2,3-dihydrobenzofuran-6-yl)-1H-indole-3-carboxylic acid

A 0.25 M solution of 6-bromo-2,3-dihydrobenzofuran was prepared indioxane. A 0.30 M solution of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylatewas also prepared in dioxane. Lastly, a 1.00 M solution of K₃PO₄ wasprepared in water. In a vial was added 400 uL of the 0.30 M dioxanesolution of 6-bromo-2,3-dihydrobenzofuran (100 umol, 1.00 eq). 400 uL ofthe 0.25 M dioxane solution of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(120 umol, 1.20 eq) was then added followed by the addition of 200 uL ofthe 1.00 M aqueous solution of K₃PO₄ (200 umol, 2.00 eq). Under nitrogenatmosphere was added (1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (3.9 mg, 6.0 umol, 0.06 eq). The vial was caped andshook for 2 hours at 120° C. The reaction was filtered and concentratedby Speedvac. The residue was washed with saturated aqueous sodiumbicarbonate and extracted with ethyl acetate (1 mL, 3×). The organiclayer was collected and dried over anhydrous sodium sulfate, filtered,and concentrated to give crude methyl6-chloro-5-(2,3-dihydrobenzofuran-6-yl)-1H-indole-3-carboxylate. To thecrude intermediate was added anhydrous tetrahydrofuran (1.5 mL) followedby Me₃SiOK (128 mg, 1000 umol, 10.0 eq). The vial was capped and shakenat 80° C. for 16 hours. The reaction was concentrated by Speedvac andthe residue was purified by preparative HPLC to provide the titlecompound. MS (ES+) 314 (M+H)⁺. Retention time: 2.56 min. Column: AgellaVenusil ASB dC18 150×21.2 mm, 5 μm. Modifier: TFA 0.225%. Gradient: 66%H₂O/34% MeCN linear to 36% H₂O/64% MeCN over 10.0 min., HOLD at 100%MeCN to 1.0 min. Flow: 30.0 mL/min.

Example 586-chloro-5-[3-fluoro-4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carboxylicacid

Step 1 methyl6-chloro-5-[3-fluoro-4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carboxylate

To a mixture of 3-(4-bromo-2-fluorophenoxy)propan-1-ol (93 mg, 0.37mmol), methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(100 mg, 0.31 mmol) and potassium carbonate (128 mg, 0.93 mmol) inToluene/EtOH (5 mL, 3:1) and water (1 ml) was added Pd(dppf)Cl₂ (22 mg,0.031 mmol). The mixture was degassed and purged with nitrogen for 5minutes, then allowed to heat to 110° C. and stirred for 30 minutes. Thereaction mixture was concentrated in vacuo to give a brown residue. Theresidue was purified by flash chromatography to give the title compound(85 mg, 73% yield) as a pale solid. ¹H NMR (400 MHz, CD₃OD) δ 8.04 (d,2H), 7.61 (m, 2H), 7.18 (m, 2H), 4.21 (m, 2H), 3.89 (s, 3H), 3.82 (t,2H), 2.08 (m, 2H).

Step 26-chloro-5-[3-fluoro-4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carboxylicacid

To a mixture of methyl6-chloro-5-[3-fluoro-4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carboxylate(85 mg, 0.23 mmol) in methanol (5 mL) and water (2 mL) was added sodiumhydroxide (90 mg, 2.3 mmol). The reaction mixture was heated at 70° C.and stirred for 24 hours. The mixture was acidified by 1N HCl to pH 4and extracted with ethyl acetate (10 mL×3). The combined organic layerswas dried over sodium sulfate, filtered, and concentrated in vacuo togive a brown residue. It was purified by preparative HPLC to give thetitle compound (31 mg, 52% yield) as a white solid. MS (AP−) 386.1(M+Na)⁻. ¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 1H), 11.98 (s, 1H), 8.08(s, 1H), 7.925 (s, 1H), 7.62 (s, 1H), 7.25-7.15 (m, 3H), 4.59 (t, 1H),4.16 (t, 2H), 3.58 (q, 2H), 1.90 (m, 2H).

Example 596-chloro-5-[4-(3-hydroxypropoxy)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

Step 1 methyl6-chloro-5-[4-(3-hydroxypropoxy)-3-methoxyphenyl]-1H-indole-3-carboxylate

To a mixture of 3-(4-bromo-2-methoxyphenoxy)propan-1-ol (97 mg, 0.37mmol), methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(100 mg, 0.31 mmol) and potassium carbonate (128 mg, 0.93 mmol) intoluene/EtOH (5 mL, 3:1) and water (1 ml) was added Pd(dppf)Cl₂ (22 mg,0.031 mmol). The mixture was degassed and purged with nitrogen for 5minutes, then allowed to heat to 110° C. and stirred for 30 minutes. Thereaction mixture was concentrated in vacuo to give a brown residue. Theresidue was purification by flash chromatography to give the titlecompound (92 mg, 76% yield) as a pale solid. ¹H NMR (400 MHz, CD₃OD) δ8.01 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.03 (m, 2H), 7.00 (m, 1H),4.18 (m, 2H), 3.87 (s, 3H), 3.80 (m, 2H), 3.37 (s, 3H), 2.05 (m, 2H).

Step 26-chloro-5-[4-(3-hydroxypropoxy)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

To a mixture of methyl6-chloro-5-[4-(3-hydroxypropoxy)-3-methoxyphenyl]-1H-indole-3-carboxylate(92 mg, 0.24 mmol) in MeOH (5 mL) and water (2 mL) was added NaOH (94mg, 2.4 mmol). The reaction mixture was heated at 70° C. and stirred for24 hours. TLC (petroleum ether/ethyl acetate=1:1) showed the reactionwas complete. The mixture was acidified by 1N HCl to pH 4 and extractedwith ethyl acetate (10 mL×3). The combined organic layers was dried oversodium sulfate, filtered, and concentrated in vacuo to give a brownresidue. It was purified by preparative HPLC to give the title compound(35 mg, 35% yield) as a white solid.

MS (AP−) 398.1 (M+Na)⁻. ¹H NMR (400 MHz, DMSO-d₆) δ 11.93 (s, 1H), 8.07(s, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 7.02 (d, 1H), 6.97 (s, 1H) 6.89(dd, 1H), 4.04 (t, 2H), 3.77 (s, 3H), 3.51 (t, 2H), 1.88 (m, 2H).

Example 606-chloro-5-[4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

Step 1 3-(4-bromo-2-methoxyphenyl)oxetan-3-ol

To a solution of 5-bromo-2-iodoanisole (533 mg, 1.30 mmol) andoxetan-3-one (0.12 mL, 2.0 mmol) in tetrahydrofuran (5 mL) at −78° C.followed by the addition of n-butyl lithium (2.5M in hexane, 0.56 mL,1.4 mmol) dropwise over 5 minutes. The reaction mixture was stirred at−78° C. for 2 hours. The reaction mixture was quenched with saturatedaqueous ammonium chloride, warmed to room temperature and extracted twotimes with ethyl acetate. The combined organic layers were dried oversodium sulfate, filtered, and concentrated under reduced pressureyielding 476 mg of crude material. The crude material was purified usingthe Biotage Isolera One (SNAP 25 g silica gel column) and eluting with agradient of 0-70% ethyl acetate/heptane yielding 137 mg (41% yield) ofthe title compound. ¹H NMR (500 MHz, CDCl₃) δ 7.15 (dd, J=8.1, 1.7 Hz,1H), 7.13 (d, J=8.1 Hz, 1H), 7.07 (d, J=1.5 Hz, 1H), 4.99 (d, J=7.1 Hz,2H), 4.84 (d, J=7.3 Hz, 2H), 3.87 (s, 3H)

Step 2 methyl6-chloro-5-[4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl]-1H-indole-3-carboxylate

To a solution of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(70 mg, 0.27 mmol) and 3-(4-bromo-2-methoxyphenyl)oxetan-3-ol (96 mg,0.30 mmol) in toluene (1.2 mL), ethanol (0.6 mL), and tetrahydrofuran(0.6 mL) followed by the addition of 2M potassium carbonate aqueous (0.6mL, 1 mmol). Nitrogen was bubbled through the reaction for 5 minutesthen [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium,dichloromethane (25 mg, 0.031 mmol) was added and the reaction heated to115° C. for 16 hours. The reaction was then cooled to room temperatureand filtered through a pad of celite washing with ethyl acetate. Thefiltrate was concentrated under reduced pressure and passed throughsilica yielding 104 mg of the title compound that was brought forwardwithout further purification. MS (ES+) 386.1 (M−H)⁺.

Step 36-chloro-5-[4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

To a mixture of methyl6-chloro-5-[4-(3-hydroxyoxetan-3-yl)-3-methoxyphenyl]-1H-indole-3-carboxylate(100 mg, 0.258 mmol) in methanol (3 mL) and sodium hydroxide (1 M, 1.0mL, 1.0 mmol) was heated to 70° C. for 24 hours. The reaction wasconcentrated under reduced pressure and the reaction was acidified with1 M hydrochloric acid aqueous to pH=2 then diluted with ethyl acetate.The layers were separated and the aqueous extracted with ethyl acetatetwo additional times. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated under reduced pressure yielding 83mg of the crude desired product. A portion of the crude material (60 mg)was purified by prep-HPLC (Phenomenex HILIC (Diol) 250×21.2 mm 5 μm;Mobile phase A: heptane; Mobile Phase B: Ethanol, gradient 95% A/5% Bhold for 1.5 minutes, linear gradient to 0% A/100% B in 8.5 minutes,Hold at 0% A/100% B for 1 minutes; flow rate: 28 ml/min) to afford thetitle compound (16.9 mg, 17.5%) as a solid. MS (ES−) 372.0 (M−H)⁻. ¹HNMR (500 MHz, DMSO-d₆) δ 12.13 (br. s, 1H), 11.96 (br. s, 1H), 8.10 (d,J=2.2 Hz, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.05(d, J=1.5 Hz, 1H), 6.99 (dd, J=7.6, 1.5 Hz, 1H), 5.89 (s, 1H), 5.02 (d,J=6.8 Hz, 2H), 4.67 (d, J=6.8 Hz, 2H), 3.81 (s, 3H)

Example 616-chloro-5-[4-(1-hydroxycyclobutyl)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

Step 1 1-(4-bromo-2-methoxyphenyl)cyclobutanol

To a solution of 5-bromo-2-iodoanisole (10.0 g, 31.9 mmol) andcyclobutanone (3.6 mL, 48 mmol) in tetrahydrofuran (107 mL) at −78° C.followed by the addition of n-butyl lithium (2.5 M in hexane, 15.6 mL,39.0 mmol) dropwise over 20 minutes. The reaction mixture was stirred at−78° C. for 2.5 hours. The reaction mixture was quenched with saturatedaqueous ammonium chloride and the reaction mixture was warmed to roomtemperature and extracted two times with ethyl acetate. The combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure yielding 9.73 g of crude material.The crude material was purified using the Biotage Isolera One (SNAP 100g silica gel column) and eluting with a gradient of 0-70% ethylacetate/heptane yielding 4.75 g (57.9% yield) of the title compound.

GC/MS: 257. ¹H NMR (500 MHz, CDCl₃) δ 7.19-7.14 (m, 1H), 7.12-7.01 (m,1H), 7.04 (d, J=2.0 Hz, 1H), 3.88 (s, 3H), 2.53-2.40 (m, 2H), 2.39-2.28(m, 2H), 2.11-2.00 (m, 1H), 1.67-1.55 (m, 1H).

Step 2 methyl6-chloro-5-[4-(1-hydroxy-cyclobutyl)-3-methoxy-phenyl]-1H-indole-3-carboxylate

A mixture of methyl6-Chloro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-1H-indole-3-carboxylate(50 mg, 0.16 mmol), 1-(4-Bromo-3-methoxy-phenyl)cyclobutanol (52 mg, 0.2mmol), 2 M aqueous potassium carbonate (0.31 mL, 0.63 mmol), toluene (3mL), and ethanol (1 mL) was sparged with nitrogen for 10 minutes, thentreated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (6 mg, 0.007 mmol). The reaction mixture washeated to 100° C. and stirred. After 2 hours the reaction was cooled toroom temperature, diluted with ethyl acetate, washed with water andsaturated brine, dried over magnesium sulfate, filtered and concentratedin vacuo to afford a yellow oil, which was purified by flashchromatography (12 g silica, 0-35% ethyl acetate/heptane, 24 columnvolumes). Product fractions were combined and concentrated in vacuo toafford the title compound as a colorless solid (19 mg, 32% yield). MS(ES−) 341.2 (M−H)⁻; ¹H NMR (500 MHz, CD₃OD) δ 8.03 (d, J=1.95 Hz, 2H),7.60 (s, 1H), 7.38 (d, J=7.56 Hz, 1H), 7.06 (d, J=1.46 Hz, 1H), 7.01(dd, J=7.68, 1.59 Hz, 1H), 3.89 (d, J=7.32 Hz, 6H), 2.65-2.75 (m, 2H),2.34-2.44 (m, 2H), 2.08-2.19 (m, 1H), 1.70-1.80 (m, 1H).

Step 36-Chloro-5-[4-(1-hydroxy-cyclobutyl)-3-methoxy-phenyl]-1H-indole-3-carboxylicacid

Methyl6-Chloro-5-[4-(1-hydroxy-cyclobutyl)-3-methoxy-phenyl]-1H-indole-3-carboxylate(19 mg, 0.05 mmol) was dissolved in methanol (3 mL) and 1N aqueoussodium hydroxide (1 mL, 1 mmol), and the mixture was stirred at 70° C.for 22 hours. The mixture was cooled to room temperature and treatedwith saturated ammonium chloride (0.5 mL) and concentrated in vacuo toafford 18 mg colorless solid, which was purified by reversed-phase HPLCto afford the title compound (8.0 mg, 44% yield). MS (ES−) 370.1626(M−H)⁻. retention time=1.67 min; Column: Waters Atlantis dC18 4.6×50 mm,5 μm; Modifier: TFA 0.05%; Gradient: 95% H₂O/5% MeCN linear to 5%H₂O/95% MeCN over 4.0 min, HOLD at 5% H₂O/95% MeCN to 5.0 min; Flow: 2.0mL/min.

Example 626-chloro-5-[4-(1-hydroxycyclobutyl)-2-methoxyphenyl]-1H-indole-3-carboxylicacid

Step 1 1-(4-Bromo-3-methoxy-phenyl)cyclobutanol

To a solution of 2-bromo-5-iodoanisole (400 mg, 1.28 mmol) intetrahydrofuran (5 mL) at −78° C. was added n-butyl lithium (2.5 M inhexane, 0.62 mL, 1.55 mmol) dropwise over 15 minutes. The reactionmixture was stirred at −78° C. for 30 minutes, then treated with neatcyclobutanone (0.1 mL, 1.3 mmol) dropwise over 10 minutes and stirred at−78° C. for an additional 1.5 hours. The reaction was quenched withsaturated aqueous ammonium chloride solution, warmed to room temperatureand extracted with ethyl acetate (2×). The combined organic layers weredried over magnesium sulfate, filtered and concentrated in vacuo toafford a yellow oil, which was purified by flash chromatography (12 gsilica, 0-50% ethyl acetate/heptane, 27 column volumes). Productfractions were combined and concentrated in vacuo to afford the titlecompound as a pale yellow oil (40 mg, 12% yield). GCMS 256/258 (M)⁺; ¹HNMR (500 MHz, CDCl₃) δ 7.53 (d, J=8.29 Hz, 1H), 7.09 (d, J=1.95 Hz, 1H),6.98 (dd, J=8.17, 1.83 Hz, 1H), 3.94 (s, 3H), 2.51-2.61 (m, 2H),2.35-2.46 (m, 2H), 2.02-2.10 (m, 1H), 1.66-1.79 (m, 1H).

Step 2 methyl6-chloro-5-[4-(1-hydroxy-cyclobutyl)-2-methoxy-phenyl]-1H-indole-3-carboxylate

A mixture of methyl6-Chloro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-1H-indole-3-carboxylate(50 mg, 0.16 mmol), 1-(4-Bromo-3-methoxy-phenyl)cyclobutanol (40 mg,0.16 mmol), 2M aqueous potassium carbonate (0.31 mL, 0.63 mmol), toluene(3 mL), and ethanol (1 mL) was sparged with nitrogen for 10 minutes,then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (6 mg, 0.007 mmol). The reaction mixture washeated to 100° C. and stirred. After 2 hours the reaction was cooled toroom temperature, diluted with ethyl acetate, washed with water andsaturated brine, dried over magnesium sulfate, filtered and concentratedin vacuo to afford 60 mg brown foam, which was purified by flashchromatography (12 g silica, 0-95% ethyl acetate/heptane, 35 columnvolumes). Product fractions were combined and concentrated in vacuo toafford the title compound as a colorless solid (6.0 mg, 10% yield). MS(ES−) 384.2 (M−H)⁻; ¹H NMR (500 MHz, CD₃OD) δ 8.01 (s, 1H), 7.91 (s,1H), 7.55 (s, 1H), 7.21 (s, 1H), 7.17-7.19 (m, 2H), 3.87 (s, 3H), 3.79(s, 3H), 2.59-2.67 (m, 2H), 2.38-2.47 (m, 2H), 2.02-2.12 (m, 1H),1.75-1.86 (m, 1H).

Step 36-chloro-5-[4-(1-hydroxy-cyclobutyl)-2-methoxy-phenyl]-1H-indole-3-carboxylicacid

Methyl6-Chloro-5-[4-(1-hydroxy-cyclobutyl)-2-methoxy-phenyl]-1H-indole-3-carboxylate(6 mg, 0.02 mmol) was dissolved in methanol (1 mL) and 1N aqueous sodiumhydroxide (0.2 mL, 0.2 mmol), and the mixture was stirred at 75° C. for22 hours. The mixture was cooled to room temperature and treated withsaturated ammonium chloride (0.5 mL) and concentrated in vacuo to afford6 mg colorless solid, which was purified by reversed-phase HPLC toafford the title compound (2.7 mg, 50% yield). MS (ES−) 370.2 (M−H)⁻.retention time=1.55 min; Column: Waters Atlantis dC18 4.6×50 mm, 5 μm;Modifier: TFA 0.05%; Gradient: 95% H₂O/5% MeCN linear to 5% H₂O/95% MeCNover 4.0 min, HOLD at 5% H₂O/95% MeCN to 5.0 min; Flow: 2.0 mL/min.

Example 63 5-(4-azetidin-2-yl-phenyl)-6-chloro-1H-indole-3-carboxylicacid

Step 1 methyl5-(4-azetidin-2-yl-phenyl)-6-chloro-1H-indole-3-carboxylate

A mixture of methyl6-Chloro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-1H-indole-3-carboxylate(50 mg, 0.16 mmol), 2-(4-bromophenyl)azetidine hydrochloride (400 mg,1.24 mmol), 2M aqueous potassium carbonate (3.11 mL, 6.22 mmol), toluene(9 mL), and ethanol (3 mL) was sparged with nitrogen for 10 minutes,then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (46 mg, 0.056 mmol). The reaction mixture washeated to 100° C. and stirred. After 2 hours the reaction was cooled toroom temperature, diluted with ethyl acetate, washed with water andsaturated brine, dried over magnesium sulfate, filtered and concentratedin vacuo to afford a yellow oil, which was purified by flashchromatography (40 g silica, 0-40% methanol/ethyl acetate (1% TEAmodifier), 24 column volumes). Product fractions were combined andconcentrated in vacuo to afford the title compound as a yellow solid(207 mg, 49% yield). MS (ES+) 341.2 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD) δ7.98 (d, J=3.90 Hz, 2H), 7.56 (s, 1H), 7.41 (s, 4H), 5.02 (t, J=8.17 Hz,1H), 3.84 (s, 3H), 3.68-3.79 (m, 1H), 3.34-3.45 (m, 1H), 2.47-2.66 (m,2H).

Step 2 5-(4-Azetidin-2-yl-phenyl)-6-chloro-1H-indole-3-carboxylic acid

Methyl 5-(4-Azetidin-2-yl-phenyl)-6-chloro-1H-indole-3-carboxylate (80mg, 0.24 mmol) was dissolved in methanol (4 mL) and 1N aqueous sodiumhydroxide (1 mL, 1 mmol), and the mixture was stirred at 70° C. for 22hours. The mixture was cooled to room temperature and treated withsaturated ammonium chloride (0.5 mL) and concentrated in vacuo to afford77 mg yellow solid, which was purified by reversed-phase HPLC to affordthe title compound (8 mg, 10% yield). MS (ES−) 325. 2 (M−H)⁻. retentiontime=1.44 min; Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Modifier:TFA 0.05%; Gradient: 95% H₂O/5% MeCN linear to 5% H₂O/95% MeCN over 4.0min, HOLD at 5% H₂O/95% MeCN to 5.0 min; Flow: 2.0 mL/min.

Example 646-chloro-5-[4-(2-oxopyrrolidin-1-yl)phenyl]-1H-indole-3-carboxylic acid

Step 1 1-(4-bromophenyl)pyrrolidin-2-one

The mixture of pyrrolidin-2-one (1.3 g, 15 mmol), 1-bromo-4-iodobenzene(2.8 g, 9.8 mmol), copper iodide (0.19 g, 0.98 mmol), cesium fluoride(3.7 g, 25 mmol) and N,N′-dimethylethylenediamine (186 mg, 0.196 mmol)in 1,4-dioxane (100 mL) was evacuated and back-filled with nitrogenthree times. The reaction mixture was stirred at room temperature for 48hours. The mixture was filtered and the filtrate was concentrated togive a white solid. The solid was purified by combi flash silica gelchromatography to give the title compound (1.1 g, 46% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃): δ 7.52 (d, 2H), 7.48 (d, 2H), 3.83 (t,2H), 2.59 (t, 2H), 2.18 (m, 2H).

Step 2 methyl6-chloro-5-[4-(2-oxopyrrolidin-1-yl)phenyl]-1H-indole-3-carboxylate

To a mixture of 1-(4-bromophenyl)pyrrolidin-2-one (120 mg, 0.50 mmol),methyl-6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(160 mg, 0.50 mmol) and potassium acetate (147 mg, 1.50 mmol) in1,4-dioxane (3 mL) was added PddppfCl₂ (36.5 mg, 0.050 mmol). Themixture was degassed and purged with nitrogen for 5 minutes, thenallowed to heat to 100° C. and stirred under microwave irradiation for40 minutes. The reaction mixture was concentrated in vacuo to give abrown residue. The residue was purified by combi flash silica gelchromatography to give the title compound (112 mg, 61% yield) as a whitesolid.

Step 36-chloro-5-[4-(2-oxopyrrolidin-1-yl)phenyl]-1H-indole-3-carboxylic acid

To a mixture of methyl6-chloro-5-[4-(2-oxopyrrolidin-1-yl)phenyl]-1H-indole-3-carboxylate (112mg, 0.30 mmol) in methanol (3 mL) and water (3 mL) was added sodiumhydroxide (36 mg, 0.94 mmol). The reaction mixture was heated at 75° C.and stirred for 48 hours. The mixture was acidified to pH=4 using 1 Nhydrochloric acid and concentrated to give a brown solid. It waspurified by reverse phase HPLC to give the title compound (40 mg, 37%yield) as a pale solid. MS (ES+) 355.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 12.11 (br. s, 1H), 11.95 (br. s, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 7.75(d, 2H), 7.62 (s, 1H), 7.43 (d, 2H), 3.89 (t, 2H), 2.53 (m, 2H), 2.09(m, 2H).

Example 655-[4-(1-acetylpiperidin-4-yl)phenyl]-6-chloro-1H-indole-3-carboxylicacid

Step 1 1-[4-(4-bromophenyl)piperidin-1-yl]ethanone

To a solution of 4-(4-bromophenyl)piperidine (400 mg, 1.70 mmol) indichloromethane (20 mL) was added triethylamine (340 mg, 3.40 mmol) andacetic anhydride (500 mg, 5.10 mmol). The mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure to give a crude residue. The material was partitionedbetween water (20 mL) and ethyl acetate (20 mL). The layers wereseparated and the aqueous layer was washed two additional times withethyl acetate (30 mL). The combined organics layers were dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give the title compound (260 mg, 60% yield) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 7.27 (d, 2H), 6.91 (d, 2H), 4.63 (d, 1H), 3.77(d, 1H), 3.00 (t, 1H), 2.57-2.42 (t, 2H), 1.97 (s, 3H), 1.75-1.68 (m,2H), 1.47-1.40 (m, 2H).

Step 2 methyl5-[4-(1-acetylpiperidin-4-yl)phenyl]-6-chloro-1H-indole-3-carboxylate

To a solution of 1-[4-(4-bromophenyl)piperidin-1-yl]ethanone (200 mg,0.70 mmol) in 1,4-dioxane/H₂O (5 mL/1 mL) was addedmethyl-6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(183 mg, 1.20 mmol), potassium carbonate (270 mg, 2.10 mmol) andPddppfCl₂ (50 mg, 0.070 mmol). The reaction mixture was degassed withnitrogen and the mixture was heated to 90° C. for 30 minutes. Thereaction was concentrated under reduced pressure to give a crudeproduct. The material was partitioned between water (20 mL) and ethylacetate (20 mL). The layers were separated and the aqueous layer waswashed two additional times with ethyl acetate (30 mL). The combinedorganics layers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to to give the title compound (240mg, 83% yield) which was used in the next step without furtherpurification.

Step 35-[4-(1-acetylpiperidin-4-yl)phenyl]-6-chloro-1H-indole-3-carboxylicacid

To a solution of methyl5-[4-(1-acetylpiperidin-4-yl)phenyl]-6-chloro-1H-indole-3-carboxylate(120 mg, 0.30 mmol) in MeOH (4 mL) was added sodium hydroxide (1 mL, 1M). The mixture was heated to 70° C. for 24 h. Solvent was removed underreduced pressure. The residue was acidified to pH=5 and dried in vacuumto give an oil, which was purified by preparative HPLC to give the titlecompound (35 mg, 30% yield) as an off-white solid.

MS (ES+) 396.9 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 1H), 11.95(s, 1H), 8.08 (d, 1H), 7.94 (s, 1H), 7.63 (s, 1H), 7.39-7.32 (m, 4H),4.56 (d, 1H), 3.95 (d, 1H), 3.35-3.19 (m, 1H), 3.86-3.83 (m, 1H),2.80-2.64 (m, 1H), 2.03 (s, 3H), 1.89-1.82 (m, 2H), 1.70-1.47 (m, 2H).

Example 666-chloro-5-[4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

Step 1 Diethyl 2-(4-bromo-2-methoxyphenyl)malonate

A mixture of 4-bromo-1-iodo-2-methoxybenzene (1100 mg, 3.5 mmol),diethylmalonate (1240 mg, 7.70 mmol), cesium carbonate (1830 mg, 5.60mmol), 2-picolinic acid (62 mg, 0.39 mmol), copper (I) iodide (34 mg,0.18 mmol), and dioxane (7 ml) was stirred at 55° C. for 2 days. A veryheavy slurry formed, LCMS indicates that the starting iodoarene is about70% consumed. The mixture was cooled to room temperature and dilutedwith 30 mL of water and extracted with ethyl acetate. The extract waswashed with water, brine, dried over magnesium sulfate, and concentratedto obtain the title compound which was about 60% pure by LCMS and wasused for the next step without purification. GCMS (ES+) 344 (M⁺).

Step 2 Ethyl 2-(4-bromo-2-methoxyphenyl)acetate

A mixture of diethyl 2-(4-bromo-2-methoxyphenyl)malonate (1213 mg, 3.500mmol), lithium chloride (620 mg, 14.6 mmol), and DMSO (6 ml) was stirredat 120° C. for 20 hours, then at 150° C. for 4 hours, and again at 120°C. for 20 hours. The reaction was cooled to room temperature, dilutedwith 25 mL of water, and extracted with ethyl acetate-heptane mixture(1:1). The extract was washed with brine (2 times), dried over magnesiumsulfate, and loaded on silica gel. Chromatography on a silica gelcolumn, eluting with a gradient from 0% to 30% of ethyl acetate inheptane gave the title compound (405 mg, 42% yield over two steps). GCMS(ES+) 272 (M⁺).

Step 3 Ethyl 2-(4-bromo-2-methoxyphenyl)-2-methylpropanoate

To a stirred solution of ethyl 2-(4-bromo-2-methoxyphenyl)acetate (105mg, 0.38 mmol) in THF (4 mL) were added successively, in drops, 1 Msolution of t-BuOK in THF (1.2 mL, 1.2 mmol) and iodomethane (0.10 mL,1.6 mmol) at 0° C. The resulting mixture was warmed to room temperaturein 30 min and stirred for 2 hours—the starting ester is consumed, thetarget product formed formed (TLC, GCMS). To the obtained mixture 1 Msolution of potassium bisulfate (2 mL) was added followed by addition ofwater (5 mL). The mixture was extracted with ethyl acetate. The organicextract was washed with brine, dried over anhydrous magnesium sulfate,and concentrated to obtain the title compound (110 mg, 95% yield), whichwas used for the next step without purification. GCMS (ES+) 300 (M⁺). ¹HNMR (500 MHz, CDCl₃) δ 7.15 (s, 1H), 7.11 (d, J=1.5 Hz, 1H), 6.98 (d,J=2.0 Hz, 1H), 4.11 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 1.50 (s, 6H), 1.17(t, J=7.1 Hz, 3H).

Step 4 2-(4-Bromo-2-methoxyphenyl)-2-methylpropan-1-ol

To a stirred solution of ethyl2-(4-bromo-2-methoxyphenyl)-2-methylpropanoate (110 mg, 0.36 mmol) inTHF (4 mL) was added 1 M solution of lithium aluminum hydride in THF(0.4 mL, 0.4 mmol) at −60° C. and the reaction mixture was warmed up to0° C. in 40 min (the starting material is still present by TLC) and thenallowed to stir at room temperature for 4 hours—now the startingmaterial is consumed (TLC). A solution of sodium hydroxide (105 mg) inwater (0.2 mL) was added and the mixture was stirred at room temperaturefor 30 min. Then 3 mL of methylene chloride (3 mL), silica gel (1 g),and anhydrous magnesium sulfate (1 g) were added and the mixture wasstirred for 2 hours. Solids were filtered off and mother liquor wasconcentrated to give the title compound (85 mg). By GCMS, this is amixture of the target primary alcohol and de-brominated primary alcohol(40% of the desired product by GCMS). This mixture was used for the nextstep without purification. GCMS (ES+) 258 (M⁺).

Step 5 Methyl6-chloro-5-(4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylate

A mixture of 2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol (crudeproduct from Step 4, containing 40% of the desired material, 75 mg, 0.12mmol), methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(45 mg, 0.14 mmol), PdCl₂(dppf) (11 mg, 0.013 mmol), potassium carbonate(80 mg, 0.58 mmol), toluene (0.6 mL), ethanol (0.3 mL), water (0.3 mL),and THF (0.3 mL) was stirred at 115° C. for 2.5 hours. The reactionmixture was cooled to room temperature and extracted with ethyl acetate(4 mL) of ethyl acetate. The extract was loaded on silica gel.Chromatography on a silica gel column, eluting with a gradient from 10%to 40% of ethyl acetate in heptane gave the title compound (25 mg, 56%yield). MS (ES−) 386.2 (M−H)⁻. Retention time: 3.38 min. Column:Phenomenex Gemini-NX, 4.6 mm×50 mm, C18, 3 μm, 110A; Column Temperature60° C. Mobile Phase A: 0.1% formic acid in water (v/v); Mobile Phase B:0.1% formic acid in acetonitrile (v/v) Gradient Profile: Flow-1.5mL/min. Initial conditions: A-95%, B-5%; Linear Ramp to A-0%, B-100%over 0.0-4.10 min; hold at A-0%, B-100% from 4.10-4.50 min; return toinitial conditions 4.60-5.0 min.

Step 66-Chloro-5-[4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

A mixture of the methyl6-chloro-5-(4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxyphenyl)-1H-indole-3-carboxylate(25 mg, 0.064 mmol), 2.4 ml of methanol (2.4 mL), and 0.8 mL of 1 Maqueous solution of sodium hydroxide (0.8 mL, 0.8 mmol) was stirred at70° C. for 24 hours—the starting material is consumed by TLC and LCMS.The reaction mixture was cooled to room temperature, diluted with 1 Msolution of potassium bisulfate (1 mL) and the obtained mixture wasconcentrated. The residue was partitioned between ethyl acetate andwater. The organic extract was washed with brine, dried over anhydrousmagnesium sulfate and loaded on silica gel. A silica gel column wasequilibrated with 30% ethyl acetate in heptane. Chromatography on thiscolumn, eluting with a solution of 3% of acetic acid and 30% of ethylacetate in heptane gave the title compound (18 mg, 73% yield). MS (ES−)372.1 (M−H)⁻. Retention time: 3.00 min Column: Phenomenex Gemini-NX, 4.6mm×50 mm, C18, 3 μm, 110A; Column Temperature 60° C. Mobile Phase A:0.1% formic acid in water (v/v); Mobile Phase B: 0.1% formic acid inacetonitrile (v/v) Gradient Profile: Flow-1.5 mL/min. Initialconditions: A-95%, B-5%; Linear Ramp to A-0%, B-100% over 0.0-4.10 min;hold at A-0%, B-100% from 4.10-4.50 min; return to initial conditions4.60-5.0 min.

Example 67 6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylicacid

Step 1 methyl6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylate

A glass tube was charged with4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-ol(86.2 mg, 0.29 mmol), methyl 5-bromo-6-chloro-1H-indole-3-carboxylate(84 mg, 0.29 mmol), toluene (1.2 mL), THF (0.6 mL), EtOH (0.6 mL), and2.0 M potassium carbonate solution (0.6 mL, 1.2 mmol). Nitrogen was thenbubbled through the mixture for 5 minutes then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28 mg,0.032 mmol) was added. The tube was sealed and heated to 115° C. for 2hours. The reaction was cooled to room temperature, opened, andneutralized with 1.0 M sodium hydrogensulfate then diluted with ethylacetate. The layers were separated and the aqueous extracted with ethylacetate (×2). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. Flash columnchromatography (20% to 100% ethyl acetate/heptane) was then used to toprovide the title compound as a white solid (80 mg, 73% yield). MS (ES−)376.1 (M−H). ¹H NMR (500 MHz, DMSO-d₆) δ 12.09 (br. s., 1H), 9.60 (s,1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.68 (s, 1H), 7.65 (d, 2H), 7.47 (d,2H), 7.34 (dd, 1H), 7.19 (dt, 1H), 6.98 (d, 1H), 6.91 (dt, 1H), 3.81 (s,3H).

Step 2 6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylic acid

A round bottomed flask was charged with methyl6-chloro-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylate (80 mg,0.21 mmol), methanol (1.8 mL), and sodium hydroxide solution (1.0 M,0.60 mL, 0.60 mmol) then heated to 70° C. with stirring for 15 h. Thereaction was then cooled to room temperature and quenched with 1.0 MHydrochloric acid and diluted with ethyl acetate. The layers wereseparated and the aqueous extracted with ethyl acetate (×3). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. Reverse phase HPLC was then used to provide thetitle compound (13 mg, 16% yield). MS (ES−) 362.0 (M−H)⁻. Retentiontime: 1.93 min Waters Xbridge dC18 5 μm 4.6×50 mm, 95% H₂O/5% MeCNlinear to 5% H₂O/95% MeCN over 4.0 min, HOLD at 5% H₂O/95% MeCN to 5.0min. (0.03% NH₄OH). Flow: 2.0 mL/min.

Example 68 6-Bromo-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylicacid

Step 1 Methyl 6-bromo-5-iodo-1H-indole-3-carboxylate

To a suspension of methyl 5-iodo-1H-indole-3-carboxylate (1.20 g, 3.09mmol) in acetic acid (30 ml) was added a solution of bromine (0.15 ml,2.9 mmol) in acetic acid (5 ml). Reaction was heated to reflux andstirred for 3 hours. The reaction was then cooled and poured onto icewater, then partitioned between water and dichloromethane. The aqueouslayer was extracted with 10% MeOH/DCM (2×100 mL). The organics werecombined, washed with brine, and dried over sodium sulfate, filtered andconcentrated to give a dark red semi solid. The residue was taken up inmethanol (30 ml). Concentrated sulfuric acid (0.5 ml) was added andmixture was heated to 70° C. for 2 days. The reaction was cooled thenconcentrated in vacuo and the residue partitioned between ethyl acetateand aqueous sodium bicarbonate solution. The layers were separated andorganic washed with brine, dried over sodium sulfate, filtered andconcentrated to give a reddish solid. The residue was dissolved inmethanol/dichloromethane and adsorbed onto silica gel and purified bysilica gel chromatography (50 g, 20-100% ethyl acetate/heptane). Themajor peak was isolated to afford a mixture of the title compound andmethyl 5-iodo-1H-indole-3-carboxylate confirmed as a brown solid (260mg) that was taken forward without further purification.

Step 2 Methyl6-bromo-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylate

To a solution of methyl 6-bromo-5-iodo-1H-indole-3-carboxylate (100 mg,0.26 mmol) in toluene (1 ml) and ethanol (1 ml) was added4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-2-ol (70 mg,0.24 mmol) followed by aqueous potassium carbonate (2 M, 1 ml, 2.0mmol). The solvent was degassed by passing nitrogen through the systemfor 5 min. Pd(dppf)Cl₂ (10 mg, 0.0053 mmol) was added then sealed andreaction heated to 110° C. The reaction was cooled then partitionedbetween water and ethyl acetate, then washed with brine, dried oversodium sulfate, filtered, concentrated in vacuo to afford the titlecompound mixed with unidentified byproducts as a dark tan solid (120mg). TLC (50% EtOAc/Heptane) indicates no separation between product andbyproducts. Crude was taken on to the next step without purification.

Step 3 6-Bromo-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylic acid

To a semi suspension of crude methyl6-bromo-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylate (120 mg,0.284 mmol) in methanol (4 ml) was added 1N NaOH (1 mL, 1 mmol) thenheated to 70° C. for 16 hrs. 5N NaOH (1 mL, 5 mmol) was then added andheating continued for 24 hrs. The reaction was cooled and quenched with4N HCl in dioxane (2 ml, 8 mmol) then concentrated to give a brown solidwhich was purified by reverse phase preparative HPLC to afford the titlecompound as a tan solid (9 mg, 8%) MS (AP−) 406.0 (M−H)⁻. ¹H NMR (400MHz, MeOH-d₄) δ: 8.10 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.63 (d, 2H),7.46 (d, 2H), 7.35 (dd, 1H), 7.17 (td, 1H), 6.86-6.98 (m, 2H).

Example 696-chloro-5-[2-cyano-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylicacid

Step 1 2-bromo-5-(1-hydroxycyclobutyl)benzonitrile

To 2-bromo-5-iodobenzonitrile (1457 mg, 4.730 mmol) in tetrahydrofuran(10 mL) at −40° C. was added isopropyl magnesium chloride.lithiumchloride (1.3 M in THF, 4.4 mL, 5.7 mmol) dropwise. The mixture wasstirred at −40° C. for 10 minutes, and was then treated withcyclobutanone (0.4 mL, 5.2 mmol) dropwise at −40° C. The reactionmixture was warmed to room temperature and stirred at that temperaturefor 16 hours. The reaction mixture was poured into water (10 mL) andextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated in vacuo to givethe title compound which was used directly in the next step withoutfurther purification.

Step 22-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-(1-hydroxycyclobutyl)benzonitrile

A suspension of 2-bromo-5-(1-hydroxycyclobutyl)benzonitrile (1193 mg,3.800 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (1680 mg,4.920 mmol), potassium acetate (1110 mg, 11.40 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (154 mg,0.189 mmol) in 1,4-dioxane (10 mL) was sealed in a microwave tube andthermally heated to 120° C. for 1 hour. The reaction mixture was pouredinto water (30 mL) and extracted with ethyl acetate (2×30 mL). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo. The crude product was purified by flashchromatography using heptanes/ethyl acetate (0:100 to 50:50) to give thetitle compound (1.0 g, 94% yield).

Step 36-chloro-5-[2-cyano-4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylicacid

A suspension of 5-bromo-6-chloro-1H-indole-3-carboxylic acid (100 mg,0.54 mmol),2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-(1-hydroxycyclobutyl)benzonitrile(124 mg, 0.435 mmol), 0.5 M aqueous potassium phosphate (1.74 mL, 0.87mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(11 mg, 0.014 mmol) in ethanol (4 mL) was sealed in a microwave tube andheated to 85° C. for 45 minutes. The reaction was diluted with water andextracted with ethyl acetate (2×10 mL). The reaction mixture wasfiltered through celite and the phases were separated. The organic phasewas dried over sodium sulfate, filtered and concentrated in vacuo andthe residue was purified by reverse phase chromatography to give thetitle compound. MS (ES−) 365.1 (M−H)⁻. Retention time: 1.60 min. Column:Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95%H₂O/5% MeCN linear to 5% H₂O/95% MeCN over 4.0 min, HOLD at 5% H₂O/95%MeCN to 5.0 min. Flow: 2.0 ml/min.

Example 705-[4-(2-amino-2-oxoethoxy)phenyl]-6-chloro-1H-indole-3-carboxylic acid

Step 1 2-(4-bromophenoxy)acetamide

To a solution of (4-bromophenoxy)acetic acid (500 mg, 2.00 mmol) indichloromethane (10 mL) and DMF (0.2 mL) was added 2 M oxalyl choride inmethylene chloride (5 mL, 10 mmol). The reaction mixture was stirred atroom temperature for 2 hours, and the solvent was removed under reducedpressure. Ammonium hydroxide (15 mL) was added dropwise via additionalfunnel. After addition, the mixture was extracted with EtOAc (3×20 mL).The combined organic layers were dried and concentrated in vacuo to give2-(4-bromophenoxy)acetamide (350 mg, 70% yield) as a yellow solid. ¹HNMR (400 MHz, CDCl₃): δ 7.37-7.35 (m, 2H), 6.81-6.79 (m, 2H), 4.59 (s,2H).

Step 2 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole

To a solution of 5-bromo-6-chloro-1H-indole (5.0 g, 22 mmol) in DMSO (30mL) was added 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (6.4 g,28 mmol) and KOAc (10.3 g, 0.11 mol). The sealed vial was heated to 100°C. for 1 h. The reaction was quenched with water (100 mL) mL) andextracted with ethyl acetate. The combined organics were dried andconcentrated in vacuo to give the title compound (2.9 g, 55% yield) as ayellow solid.

¹H NMR (400 MHz, CDCl₃) δ 8.11 (br. s., 1H), 7.99 (s, 1H), 7.37 (s, 1H),7.14 (s, 1H), 6.51 (s, 1H), 3.83 (s, 4H), 1.08 (s, 6H).

Step 3 2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]acetamide

A mixture of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole(260 mg, 1.00 mmol) and N,N-dimethylformiminium chloride (250 mg, 2.00mmol) in dry 1,4-dioxane (5 mL) and DMF (1 mL) was sealed in a reactionvessel and stirred at room temperature for 10 minutes to give a whiteslurry. To the slurry was added 2 M aqueous potassium carbonate (2.5 mL,5 mmol), 2-(4-bromophenoxy)acetamide (240 mg, 1.00 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg). Thesealed vial was degassed with nitrogen and heated to 90° C. for 30minutes. The reaction was quenched with water (20 mL), and extractedwith EtOAc (3×20 mL). The combined organic layers were dried andconcentrated in vacuo to give2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]acetamide (250 mg, 55%yield) as a yellow solid.

Step 4 5-[4-(2-amino-2-oxoethoxy)phenyl]-6-chloro-1H-indole-3-carboxylicacid

To a mixture of 2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]acetamide(100 mg, 0.30 mmol) in acetonitrile (5 mL) and tert-butanol (5 mL) wasadded 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C.and treated with a solution of sodium chlorite (540 mg, 6.00 mmol) andsodium phosphate monobasic hydrate (850 mg, 6.00 mmol) in water (5 mL)dropwise via additional funnel. The ice bath was removed and thereaction was stirred at room temperature for 48 h. The solvent wasremoved in vacuo to give a residue, which was purified by prep-HPLC(Prep-HPLC: Column: Kromasil Eternity-5-C18 150*30 mm*5 μm Mobile phase:from 24% MeCN in water (0.225% FA) to 34% MeCN in water (0.225% FA);Wavelength: 220 nm Flow rate: 30 mL/min) to give5-[4-(2-amino-2-oxoethoxy)phenyl]-6-chloro-1H-indole-3-carboxylic acid(22 mg, 20% yield) as a white solid. MS (ES+) 344.8 (M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.01-7.99 (m, 2H), 7.57 (s, 1H), 7.43-7.39 (m, 2H),7.07-7.05 (m, 2H), 4.56 (s, 2H).

Example 71 6-chloro-5-[4-(2-hydroxyethyl)phenyl]-1H-indole-3-carboxylicacid

Step 1 6-chloro-5-[4-(2-hydroxyethyl)phenyl]-1H-indole-3-carbaldehyde

A mixture of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole(260 mg, 1.00 mmol) and N,N-dimethylformiminium chloride (250 mg, 2.00mmol) in dry 1,4-dioxane (5 mL) and DMF (1 mL) was sealed in a reactionvessel and stirred at room temperature for 10 minutes to give a whiteslurry. To the slurry was added 2 M aqueous potassium carbonate (2.5 mL,5.0 mmol), 2-(4-bromophenyl)ethanol (200 mg, 1.00 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg). Thesealed vial was degassed and heated to 90° C. for 30 min. The cooledreaction mixture was poured into water (20 mL), and extracted with EtOAc(3×20 mL). The combined organic layers were dried and concentrated invacuo to give6-chloro-5-[4-(2-hydroxyethyl)phenyl]-1H-indole-3-carbaldehyde (180 mg,68% yield) which was used in the next step without purification.

Step 2 6-chloro-5-[4-(2-hydroxyethyl)phenyl]-1H-indole-3-carboxylic acid

To a mixture of6-chloro-5-[4-(2-hydroxyethyl)phenyl]-1H-indole-3-carbaldehyde (150 mg,0.50 mmol) in acetonitrile (5 mL) and tert-butanol (5 mL) was added2-methyl-2-butene (5 mL). The reaction mixture was cooled to 0° C. andtreated with a solution of sodium chlorite (900 mg, 10.0 mmol) andsodium phosphate monobasic hydrate (1.4 g, 10 mmol) in water (5 mL)dropwise via additional funnel. Then ice bath was removed, and thereaction was stirred at room temperature for 20 hours. The solvent wasremoved in vacuo to give a residue, which was purified by pre-HPLC(Kromasil Eternity-5-C18 150×30 mm×5 μm Mobile phase: from 26% MeCN inwater (0.1% TFA) to 41% MeCN in water (0.1% TFA); Wavelength: 220 nmFlow rate: 30 mL/min) to give6-chloro-5-[4-(2-hydroxyethyl)phenyl]-1H-indole-3-carboxylic acid (35mg, 25% yield) as a white solid. MS (ES+) 337.9 (M+Na)⁺. ¹H NMR (400MHz, CD₃OD) δ 8.01-7.99 (m, 2H), 7.57 (s, 1H), 7.37 (d, 2H), 7.30 (d,2H), 3.80 (t, 2H), 2.91 (t, 2H).

Example 726-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylicacid

Step 1 1-(4-bromophenyl)cyclobutanecarboxylic acid

To a solution of 1-(4-bromophenyl)cyclobutanecarbonitrile (1.0 g, 4.2mmol) in EtOH (28 mL) and water (2 mL) was added KOH (2.1 g, 42 mmol).The reaction mixture was heated to reflux for 16 hours. The reaction wasthen quenched with 1M hydrochloric acid in order to adjust pH to 7. Theorganic solvents were removed in vacuo to give a residue, which wasdissolved in ethyl acetate (40 mL), then washed with brine (3×10 mL).The organic phase was concentrated in vacuo, and the resulting oil waspurified by flash chromatography on silica gel (petroleum ether/ethylacetate=8:1) to give 1-(4-bromophenyl)cyclobutanecarboxylic acid (0.8 g,79% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (d, 2H),7.19 (d, 2H), 2.70-2.63 (m, 2H), 2.33-2.26 (m, 2H), 1.89-1.87 (m, 1H),1.75-1.71 (m, 1H).

Step 2 [1-(4-bromophenyl)cyclobutyl]methanol

To a solution of 1-(4-bromophenyl)cyclobutanecarboxylic acid (300 mg,1.20 mmol) in 1,4-dioxane (5 mL) was added borane dimethylsulfidecomplex (0.24 mL, 2.4 mmol) dropwise at 0° C. The ice bath was removed,and the reaction mixture was stirred at room temperature for 10 min. Thereaction mixture was quenched with methanol (20 mL). The organicsolvents were removed under reduced pressure to give a residue, whichwas dissolved in ethyl acetate, then washed with brine. The organicphase was concentrated to give [1-(4-bromophenyl)cyclobutyl]methanol(170 mg, 62% yield) as a yellow oil which was used directly in the nextstep.

Step 36-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde

A mixture of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole(260 mg, 1.00 mmol) and N,N-dimethylformiminium chloride (250 mg, 2.00mmol) in dry dioxane (5 mL) and DMF (1 mL) was sealed in a reactionvessel and stirred at room temperature for 10 minutes to give a whiteslurry. To the slurry was added 2M aqueous potassium carbonate (2.5 mL,5.0 mmol), [1-(4-bromophenyl)cyclobutyl]methanol (240 mg, 1.00 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg). Thereaction mixture was degassed with nitrogen and heated to 90° C. for 30minutes. The reaction was quenched with water (20 mL) and extracted withEtOAc (3×20 mL). The combined organic phases were dried and concentratedin vacuo to give6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde(180 mg, 68% yield), which was used into next step without furtherpurification.

Step 46-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylicacid

To a mixture of6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde(80 mg, 0.24 mmol) in acetonitrile (6 mL) and tert-butanol (6 mL) wasadded 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C.and treated with a solution of sodium chlorite (420 mg, 4.80 mmol) andsodium phosphate monobasic hydrate (650 mg, 4.80 mmol) in water (3 mL)dropwise via additional funnel. The ice bath was removed, and thereaction mixture was stirred at room temperature for 24 hours. Thesolvent was removed in vacuo to give a residue, which was purified byprep-HPLC (Kromasil Eternity-5-C18 150*30 mm*5 μm Mobile phase: from 35%MeCN in water (0.1% TFA) to 50% MeCN in water (0.1% TFA); Wavelength:220 nm Flow rate: 30 mL/min) to give6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylicacid (25 mg, 32% yield) as a white solid. MS (ES+) 377.9 (M+Na)⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.01 (s, 1H), 7.97 (s, 1H), 7.57 (s, 1H), 7.39 (d,2H), 7.23 (d, 2H), 3.70 (s, 2H), 2.39-2.30 (m, 4H), 2.11-2.09 (m, 1H),1.92-1.91 (m, 1H).

Example 736-chloro-5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indole-3-carboxylic acid

Step 16-chloro-5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indole-3-carbaldehyde

To a solution of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (150 mg,0.57 mmol) in anhydrous 1,4-dioxane (5 mL) and DMF (1 mL) was addedN,N-dimethylformiminium chloride (145 mg, 1.13 mmol). The reactionmixture was stirred at room temperature for 20 minutes to give a thicksolution. The reaction mixture was then treated with 2 N aqueouspotassium carbonate (393 mg, 2.85 mmol),5-bromo-N,N-dimethylpyrimidin-2-amine (115 mg, 0.57 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg,0.068 mmol) and degassed with nitrogen for 2 minutes. The reactionmixture was heated to 90° C. for 30 minutes. After cooling to roomtemperature, the solvents were removed in vacuo and the residue waspurified by column chromatography on silica gel (EtOAc/petroleumether=1:5 to 1:1) to afford6-chloro-5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indole-3-carbaldehyde(100 mg, 58.3% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.25 (s, 1H), 9.92 (s, 1H), 8.40 (s, 2H), 8.36 (s, 1H), 8.01 (s, 1H),7.69 (s, 1H), 3.15 (s, 6H).

Step 26-chloro-5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indole-3-carboxylic acid

6-chloro-5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indole-3-carbaldehyde(100 mg, 0.333 mmol) was dissolved in acetonitrile (6 mL) and warmtert-butanol (6 mL) and treated with 2-methyl-2-butene (4 mL). Thereaction mixture was cooled to 0° C. and treated with a solution ofsodium chlorite (450 mg, 6.65 mmol) and sodium phosphate monobasicdihydrate (1.04 g, 6.65 mmol) in water (3 mL) dropwise via additionfunnel. The reaction mixture was warmed to room temperature and stirredfor 20 hours. The reaction mixture was concentrated to remove theorganics and extracted with EtOAc (3×20 mL). The combined organic layerswere washed with brine (20 mL), dried and concentrated in vacuo. Thecrude product was purified by prep-HPLC (Column: Agella venusil ASB C18150×21.2 mm×5 μm; Mobile phase: from 20% MeCN in water (0.1% HCl) to 45%MeCN in water (0.1% HCl) Wavelength: 220 nm) to give6-chloro-5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indole-3-carboxylic acid(43 mg, 41% yield) as a yellow solid. MS (ES+) 316.9 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 11.98 (s, 1H), 8.42 (s, 2H), 8.08 (d, 1H), 7.93 (s, 1H),7.65 (s, 1H), 3.17 (s, 6H).

Example 746-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1 3-(4-bromophenyl)-1-methylpyrrolidine

To a mixture of 3-(4-bromophenyl)pyrrolidine hydrochloride (200 mg, 0.76mmol) in methanol (6 mL) was added triethylamine (77 mg, 0.76 mmol) andseveral drops of acetic acid. The reaction mixture was stirred at roomtemperature for 5 min and treated with aqueous formaldehyde (37%, 0.2mL) and sodium triacetoxyborohydride (322 mg, 1.52 mmol). The reactionmixture was stirred for 18 h at room temperature. The methanol wasevaporated in vacuo and the residue was partitioned between water andEtOAc. The phases were separated and the aqueous phase wasback-extracted with EtOAc. The combined organic phases were washed withbrine, dried over Na₂SO₄, and concentrated in vacuo to give3-(4-bromophenyl)-1-methylpyrrolidine (0.247 g) as a solid, which wasused in the next step without further purification. MS (ES+) 239.9(M+H)⁺.

Step 26-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carbaldehyde

To 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (118 mg,0.446 mmol) in anhydrous 1,4-dioxane (3.7 mL) and anhydrous DMF (0.74mL) was added N,N-dimethylformiminium chloride (114 mg, 0.892 mmol). Thereaction mixture was stirred for 10 min at room temperature, yielding athick suspension. The reaction mixture was treated with 2 N aqueouspotassium carbonate (1.1 mL, 2.2 mmol),3-(4-bromophenyl)-1-methylpyrrolidine (120 mg, 0.446 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg,0.036 mmol). The resulting mixture was heated at 90° C. for 30 min. Thereaction mixture was cooled and partitioned between water and EtOAc. Theaqueous phase was extracted twice with EtOAc, and the combined organicphases were dried over sodium sulfate and concentrated in vacuo to give6-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carbaldehyde(0.23 g, 16% yield) which was used directly in the next step. MS (ES+)339.0 (M+H)⁺.

Step 36-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylicacid

To a solution of6-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carbaldehyde(crude, 0.23 g, 0.68 mmol) in acetonitrile (8 mL) and tert-butanol (8mL) was added 2-methyl-2-butene (8 mL). The reaction mixture was cooledto 0° C. and treated with a solution of sodium chlorite (683 mg, 7.50mmol) and sodium phosphate monobasic dihydrate (1.59 g, 10.2 mmol) inwater (4 mL) dropwise. The reaction mixture was stirred at roomtemperature for two hours and treated with additional sodium chlorite(911 mg, 10.0 mmol) and sodium phosphate monobasic dihydrate (2.12 g,13.6 mmol) in H₂O (4 mL) and 2-methyl-2-butene (2 mL). The resultingmixture was stirred at room temperature for 16 h. The reaction mixturewas evaporated in vacuo and the aqueous residue was extracted with EtOAc(3×30 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified via prep-HPLC to give6-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylicacid (10 mg) as a solid. MS (ES+) 354.9 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.01 (m, 2H), 7.59 (s, 1H), 7.3-7.5 (m, 4H), 3.40-4.00 (m, 5H), 3.06(s, 3H), 2.1-2.7 (m, 2H).

Example 756-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carboxylicacid

Step 16-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carbaldehyde

A mixture of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole(156 mg, 0.60 mmol) and N,N-dimethylformiminium chloride (150 mg, 1.20mmol) in dry 1,4-dioxane (4 mL) and DMF (0.7 mL) was sealed in a vialand stirred at room temperature for 10 min to give a white slurry. Tothe reaction mixture was then added 2 M aqueous potassium carbonate (2.5mL, 5 mmol), [1-(4-bromophenyl)cyclopropyl]methanol (140 mg, 0.6 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg).The reaction mixture was degassed and heated to 90° C. for 30 min. Thecooled reaction mixture was diluted with water (20 mL), and then washedwith EtOAc (3×20 mL). The combined organic layers were dried andconcentrated in vacuo to give crude6-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carbaldehyde(160 mg, 90% yield), which was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.77 (s, 1H),8.56 (s, 1H), 7.92 (s, 1H), 7.39-7.34 (m, 4H), 4.70 (br.s., 1H), 3.56(s, 2H), 0.88-0.86 (m, 2H), 0.79-0.77 (m, 2H).

Step 26-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carboxylicacid

To a mixture of6-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carbaldehyde(80 mg, 0.24 mmol) in acetonitrile (3 mL) and tert-butanol (3 mL) wasadded 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C.and treated with a solution of sodium chlorite (420 mg, 4.80 mmol) andsodium phosphate monobasic (650 mg, 4.80 mmol) in water (3 mL) dropwisevia addition funnel. The reaction mixture was warmed to room temperatureand stirred for 20 hours. The solvent was removed in vacuo to give aresidue, which was purified by prep-HPLC (Column: Boston Symmetrix ODS-H150*30 mm*5 μm Mobile phase: from 36% MeCN in water (0.1% TFA) to 36%MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min) togive6-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1H-indole-3-carboxylicacid (25 mg, 32% yield) as a white solid. MS (ES+) 364.0 (M+Na)⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 11.96 (s, 1H), 8.07 (d, 1H), 7.92(s, 1H), 7.62 (s, 1H), 7.38-7.32 (m, 4H), 4.73-4.71 (m, 1H), 3.58-3.57(m, 2H), 0.88-0.77 (m, 4H).

Example 766-chloro-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-indole-3-carboxylicacid

Step 16-chloro-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-indole-3-carbaldehyde

To a solution of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (154 mg,0.584 mmol) in anhydrous 1,4-dioxane (5 mL) and DMF (1 mL) was addedN,N-dimethylformiminium chloride (150 mg, 1.17 mmol). The reactionmixture was stirred at room temperature for 20 minutes, then treatedwith 2 M aqueous potassium carbonate (400 mg, 2.90 mmol),4-(5-bromopyrimidin-2-yl)morpholine (145 mg, 0.594 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg,0.068 mmol). The reaction was degassed with nitrogen for 2 minutes andheated to 90° C. for 30 minutes. The cooled reaction mixture wasconcentrated in vacuo and purified by column chromatography on silicagel (petroleum ether/EtOAc=1:4) to afford6-chloro-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-indole-3-carbaldehyde(159 mg, 79.4% yield) as an yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.36 (s, 1H), 10.01 (s, 1H), 8.55 (s, 2H), 8.46 (s, 1H), 8.12 (s, 1H),7.79 (s, 1H), 3.84 (m, 4H), 3.77 (m, 4H).

Step 26-chloro-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-indole-3-carboxylicacid

6-chloro-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-indole-3-carbaldehyde(159 mg, 0.464 mmol) was dissolved in acetonitrile (6 mL) and warmtert-butanol (6 mL) and treated with 2-methyl-2-butene. The reactionmixture was cooled to 0° C. and treated with a solution of sodiumchlorite (630 mg, 9.27 mmol) and sodium phosphate monobasic dihydrate(1.45 g, 9.30 mmol) in water (5 mL) via addition funnel. The mixture wasstirred at room temperature overnight. The reaction mixture was thenconcentrated in vacuo to remove the organics and extracted with EtOAc(3×20 mL). The combined organics were washed with brine (20 mL), driedand concentrated in vacuo to give a crude, which was purified byprep-HPLC to give6-chloro-5-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-indole-3-carboxylicacid (67.6 mg, 40.60% yield) as a white solid. MS (ES+) 359.1 (M+H)⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 12.03 (s, 1H), 8.49 (m, 2H),8.12 (m, 1H), 7.97 (s, 1H), 7.69 (s, 1H), 3.78 (m, 4H), 3.70 (m, 4H).

Example 776-chloro-5-{4-[2-(morpholin-4-yl)-2-oxoethyl]phenyl}-1H-indole-3-carboxylicacid

Step 16-chloro-5-{4-[2-(morpholin-4-yl)-2-oxoethyl]phenyl}-1H-indole-3-carbaldehyde

To a solution of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (153 mg,0.581 mmol) in anhydrous 1,4-dioxane (5 mL) and DMF (1 mL) was addedN,N-dimethylformiminium chloride (160 mg, 1.25 mmol). The reactionmixture was stirred at room temperature for 20 minutes, and then treatedwith 2 N aqueous potassium carbonate (1.44 mL, 2.90 mmol) and2-(4-bromophenyl)-1-(morpholin-4-yl)ethanone (165 mg, 0.58 mmol). Thereaction was degassed with nitrogen, and treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg,0.068 mmol). The reaction mixture was stirred at 90° C. for 30 minutes,cooled to room temperature, and poured into water (15 mL). The productwas extracted with ethyl acetate (3×20 mL), and the combined organicphases were dried and concentrated in vacuo to give the title compound(249 mg, >100% yield) as a red solid, which was used in the next stepwithout further purification.

Step 26-chloro-5-{4-[2-(morpholin-4-yl)-2-oxoethyl]phenyl}-1H-indole-3-carboxylicacid

To a solution of6-chloro-5-{4-[2-(morpholin-4-yl)-2-oxoethyl]phenyl}-1H-indole-3-carbaldehyde(249 mg, 0.650 mmol) in acetonitrile (6 mL) and tert-butanol (6 mL) wasadded 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C.and treated with a solution of sodium chlorite (880 mg, 13.1 mmol) andsodium phosphate monobasic dihydrate (2030 mg, 13.01 mmol) in water (3mL) via addition funnel. The icebath was removed and the mixture wasallowed to warm to room temperature. The reaction mixture was stirred atroom temperature for 18 hours. The reaction was quenched with aqueoussodium sulfite, concentrated in vacuo and extracted with ethyl acetate(4×25 mL). The combined organic phases were washed with brine (20 mL),dried and concentrated in vacuo. The crude product was purified byprep-HPLC (Column: Phenomenex Synergi C18 150*30 mm*4 μm; Mobile phase:from 38% MeCN in water (0.225% FA) to 58% MeCN in water (0.225% FA);Wavelength: 220 nm) to afford the title compound (65 mg, 28% yield) as awhite solid. MS (ES+) 399.0 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.03 (s,1H), 8.01 (s, 1H), 7.59 (s, 1H), 7.43 (d, 2H), 7.34 (d, 2H), 3.87 (s,2H), 3.65 (m, 4H), 3.52 (m, 2H), 3.55 (m, 2H).

Example 785-[4-(1-carboxycyclobutyl)phenyl]-6-chloro-1H-indole-3-carboxylic acid

Step 11-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]cyclobutanecarboxylic acid

To a solution of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (200 mg,0.80 mmol) in 1,4-dioxane (5 mL) and DMF (1 mL) was addedN,N-dimethylformiminium chloride (250 mg, 2.00 mmol). The reactionmixture was sealed and stirred at room temperature for 10 minutes. Tothe resulting slurry was added 2 M aqueous potassium carbonate (2 mL, 4mmol), 1-(4-bromophenyl)cyclobutanecarboxylic acid (255 mg, 1.00 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg).The reaction mixture was degassed with nitrogen, sealed, and heated to90° C. for 30 minutes. The reaction was quenched with H₂O (20 mL), thenwashed with ethyl acetate (3×20 mL). The combined organic phases weredried and concentrated in vacuo to give the title compound (180 mg, 63%yield) in crude form, which was used in the next step without furtherpurification. ¹H NMR (400 MHz, CD₃OD) δ 9.90 (s, 1H), 8.17 (s, 1H), 8.13(s, 1H), 7.62-7.61 (m, 1H), 7.48-7.45 (m, 2H), 7.41-7.37 (m, 2H),2.86-2.79 (m, 2H), 2.62-2.45 (m, 2H), 2.05-2.01 (m, 2H).

Step 2 5-[4-(1-carboxycyclobutyl)phenyl]-6-chloro-1H-indole-3-carboxylicacid

To a mixture of 1-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]cyclobutanecarboxylic acid (120 mg, 0.30 mmol) in acetonitrile (3 mL) andtert-butanol (3 mL) was added 2-methyl-2-butene (3 mL). The reactionmixture was cooled to 0° C. and treated with a solution of sodiumchlorite (550 mg, 6.00 mmol) and sodium phosphate monobasic (800 mg,6.00 mmol) in water (3 mL) dropwise via additional funnel. The ice waterbath was removed, and the reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture was concentrated in vacuoto give a residue, which was purified by prep-HPLC (Column: BostonSymmetrix ODS-H 150*30 mm*5 μm Mobile phase: from 39% MeCN in water(0.1% TFA) to 39% MeCN in water (0.1% TFA); Wavelength: 220 nm Flowrate: 30 mL/min;) to give the title compound (35 mg, 27% yield) as awhite solid. MS (ES+) 392.0 (M+Na)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.03 (s,1H), 7.99 (s, 1H), 7.58 (s, 1H), 7.44-7.38 (m, 4H), 2.90-2.84 (m, 2H),2.62-2.54 (m, 2H), 2.11-1.97 (m, 1H), 1.95-1.91 (m, 1H).

Example 796-chloro-5-[4-(5-oxomorpholin-2-yl)phenyl]-1H-indole-3-carboxylic acid

Step 1 N-(2-(4-bromophenyl)-2-hydroxyethyl)-2-chloroacetamide

To a solution of compound 2-amino-1-(4-bromophenyl)ethanol (2.0 g, 10mmol) in CH₂Cl₂ (40 mL) and water (40 mL) was added NaOH (0.48 g, 12mmol) and chloroacetyl chloride (1.7 g, 15 mmol) at 0° C. Afteraddition, the mixture was allowed to warm to room temperature andstirred for 6 hours. The layers were separated. The organic was washedwith 3% HCl and saturated NaHCO₃, dried over sodium sulfate, andconcentrated to afford the title compound (2.0 g, 76% yield) as a yellowsolid. ¹H NMR: (400 MHz, CDCl₃):δ 7.45 (d, 2H), 7.19 (d, 2H), 6.98 (br.s, 1H), 4.80 (m, 1H), 4.01 (s, 2H), 3.68 (m, 1H), 3.30 (m, 1H), 2.82(br. s, 1H):

Step 2 6-(4-bromophenyl)morpholin-3-one

To a solution of N-(2-(4-bromophenyl)-2-hydroxyethyl)-2-chloroacetamide(2.0 g, 6.8 mmol) in THF (20 mL) was added potassium t-butoxide (0.46 g,8.2 mmol). The mixture was stirred at room temperature overnight. Thereaction mixture was quenched with water (20 mL), extracted with ethylacetate (20 mL×3). The combined organic layers was dried over sodiumsulfate, filtered, and concentrated in vacuo to give the title compound(1.6 g, 92% yield) as a yellow solid. ¹H NMR: (400 MHz, CDCl₃): δ7.46(d, 2H), 7.20 (d, 2H), 6.56 (s, 1H), 4.67 (m, 1H), 4.35 (d, 1H), 4.24(d, 1H), 3.40 (m, 2H):

Step 36-chloro-5-[4-(5-oxomorpholin-2-yl)phenyl]-1H-indole-3-carbaldehyde

The mixture of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (150 mg,0.57 mmol) and N,N-dimethylformiminium chloride (217 mg, 1.70 mmol) inDMF/dioxane (6 mL, 1:5) was stirred at room temperature for 20 minutes.Then 2.0 M potassium carbonate (3 mL), 6-(4-bromophenyl)morpholin-3-one(146 mg, 0.57 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I I) (41 mg,0.057 mmol) was added to the mixture. The reaction mixture was purgedwith nitrogen for 3 minutes, heated to 90° C. and stirred for 30minutes. The reaction mixture was extracted with ethyl acetate (10mL×3). The organic layers were combined, dried over sodium sulfate, andconcentrated in vacuo to give the title compound (150 mg, 75% yield) asa brown solid that was brought forward without further purification.

Step 4 6-chloro-5-[4-(5-oxomorpholin-2-yl)phenyl]-1H-indole-3-carboxylicacid

To a solution of6-chloro-5-[4-(5-oxomorpholin-2-yl)phenyl]-1H-indole-3-carbaldehyde (150mg, 0.42 mmol) in acetonitrile (5 mL) and t-BuOH (5 mL) was added2-methyl-2-butene (2.9 g, 42 mmol). The mixture was cooled to 0° C. withice bath. Sodium chlorite (1.15 g, 12.7 mmol) and sodium phosphatemonobasic hydrate (1.75 g, 12.7 mmol) were dissolved in water (5 mL).The aqueous was added to the organic solution and the mixture wasallowed to warm to room temperature. The reaction mixture was stirred atroom temperature for 48 hours. A solution of sodium sulfite was addedslowly to the stirring mixture. The reaction mixture was allowed to stir1 hour. Then the organics were removed under reduced pressure. Theaqueous layer was extracted with ethyl acetate (10 mL×3). The combinedorganic layers was dried over sodium sulfate, filtered, and concentratedin vacuo to give a brown residue. The residue was purified by reversephase HPLC to give the title compound (40 mg, 26% yield) as an off-whitesolid. MS (ES+) 371.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H),8.20 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.63 (s, 1H), 7.48 (d, 2H),7.44 (d, 2H), 4.65 (m, 1H), 4.22 (s, 2H), 3.46 (m, 2H).

Example 80 6-chloro-5-[4-(3-hydroxypropyl)phenyl]-1H-indole-3-carboxylicacid

Step 1 6-chloro-5-[4-(3-hydroxypropyl)phenyl]-1H-indole-3-carbaldehyde

To a solution of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (100 mg,0.379 mmol) in dioxane (2 mL) and DMF (0.1 mL) was addedN,N-dimethylformiminium chloride (180 mg, 0.36 mmol). The resultingmixture was stirred at room temperature for 20 min. The reaction wasquenched with 2.0 N potassium carbonate (1.5 mL, 3.0 mmol), then3-(4-bromophenyl)propan-1-ol (81.5 mg, 0.379 mmol) and Pd(dppf)Cl₂ (28mg, 0.037 mmol) were added, then heated to 90° C. for 30 min. Thereaction mixture was extracted with EtOAc (3 mL×3), combined the organiclayers and concentrated in vacuo to afford the title compound (40 mg,27% yield) after purification via preparative TLC.

Step 2 6-chloro-5-[4-(3-hydroxypropyl)phenyl]-1H-indole-3-carboxylicacid

To 6-chloro-5-[4-(3-hydroxypropyl)phenyl]-1H-indole-3-carbaldehyde (40mg, 0.13 mmol) in 2-methyl-2-butene/t-butanol/water (v/v/v=1/1/1, 6 mL)was added sodium dihydrogen phosphate (30.5 mg, 0.254 mmol) and sodiumchlorite (23 mg, 0.25 mmol) at room temperature. The resulting mixturewas stirred at room temperature for 14 hours. The reaction mixture wasadded sodium sulfite (0.254 mmol), diluted with water, extracted withEtOAc, then concentrated in vacuo and purified via preparative HPLC togive the title compound (6.0 mg, 14% yield).

MS (AP−) 328.0 (M−H)⁻. ¹H NMR (400 MHz, CD₃OD) δ 6.71 (d, 2H), 6.28 (s,1H), 6.06 (d, 2H), 5.98 (d, 2H), 2.33 (t, 2H), 1.46 (m, 2H), 0.61 (m,2H).

Example 816-chloro-5-[3-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carboxylicacid

Step 16-chloro-5-[3-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde

A mixture of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole(100 mg, 0.38 mmol) and N,N-dimethylformiminium chloride (97 mg, 0.76mmol) in DMF (3 mL) and dioxane (0.6 mL) was stirred at room temperaturefor 30 min. Potassium carbonate (2 mL, 4 mmol, 2 N) was added to themixture. Then 2-(4-bromo-2-fluorophenoxy)ethanol (89 mg, 0.38 mmol) andPd(dppf)Cl₂ (20 mg, 0.03 mmol) was added to the reaction. The mixturewas degassed by passing nitrogen through the solution for 5 min. andstirred at 80° C. for 2 hrs. The reaction was cooled and concentrated.The residue was dissolved with EtOAc (100 mL), washed with water (30mL), saturated ammonium chloride (30 mL), brine (30 mL), dried oversodium sulfate and concentrated to afford a crude product. The crude wasfurther purified by silica gel chromatography (PE/EtOAc=20% to 50%) togive the title compound (40 mg, 30% yield) as a light yellow oil. ¹H NMR(400 MHz, CD₃OD) δ 9.89 (s, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.62 (s,1H), 7.20 (m, 3H), 4.18 (t, 2H), 3.93 (t, 2H).

Step 26-chloro-5-[3-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carboxylicacid

To a solution of6-chloro-5-[3-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde(40 mg, 0.12 mmol) in water (1 mL) and t-butanol (1 mL) was added sodiumchlorite (210 mg, 2.30 mmol), 2-methyl-2-butene (0.5 mL) and sodiumdihydrogen phosphate (350 mg, 2.90 mmol). The reaction solution wasstirred at room temperature for 10 hrs. The reaction was diluted withwater (5 mL) and extracted with dichloromethane (20 mL×3). The combinedorganic phase was washed with water (20 mL), brine (20 mL), dried oversodium sulfate and concentrated to give a crude product. The crude waspurified by preparative HPLC to give the title compound (20 mg, 49%yield) as off-white solid. MS (AP−) 348.0 (M−H)⁻. ¹H NMR (400 MHz,CD₃OD) δ 8.05 (s, 1H), 8.01 (s, 1H), 7.60 (s, 1H), 7.20 (m, 3H), 4.21(t, 2H), 3.95 (t, 2H).

Example 826-chloro-5-{4-[2-(methylamino)-2-oxoethoxy]phenyl}-1H-indole-3-carboxylicacid

Step 1 2-(4-bromophenoxy)-N-methylacetamide

To a solution of (4-bromophenoxy)acetic acid (500 mg, 2.10 mmol) inN,N-dimethylformamide (15 mL) was added methylamine hydrochloride (320mg, 5.10 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (570 mg,3.00 mmol), 1-hydroxybenzotriazole (400 mg, 3.00 mmol) andN-methyl-morpholine (600 mg, 6.00 mmol). The mixture was stirred at roomtemperature overnight. The reaction was quenched with water (20 mL), andthen washed three times with ethyl acetate (20 mL). The combinedorganics was dried and concentrated to give the title compound (580 mg,90% yield) that was used without further purification. ¹H NMR (400 MHz,CDCl₃) δ 7.45 (d, 2H), 6.79 (d, 2H), 6.56 (s, 1H), 4.46 (s, 2H), 2.91(d, 3H).

Step 2 2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]-N-methylacetamide

To the slurry ofmethyl-6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(240 mg, 1.0 mmol) was added 2 M potassium carbonate (2.5 mL, 5.0 mmol),2-(4-bromophenoxy)-N-methylacetamide (240 mg, 1.00 mmol) and PddppfCl₂(50 mg, 0.061 mmol). The sealed vial was heated to 90° C. for 30 min.The reaction was cooled to room temperature and quenched with water (20mL), and then washed three times with ethyl acetate (20 mL). Thecombined organics were dried and concentrated to give the title compound(250 mg, 55% yield) as a yellow solid that was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 9.94 (s, 1H), 8.37 (d, 1H),8.02 (s, 1H), 7.68 (s, 1H), 7.38 (d, 2H), 7.05 (d, 2H), 4.52 (s, 2H),2.68 (d, 3H).

Step 36-chloro-5-{4-[2-(methylamino)-2-oxoethoxy]phenyl}-1H-indole-3-carboxylicacid

To a mixture of2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]-N-methylacetamide (120mg, 0.35 mmol) in acetonitrile/t-butanol (4 mL/4 mL) was added2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C.followed by the addition of an aqueous solution of sodium chlorite (630mg, 7.00 mmol) and sodium phosphate (monobasic and monohydrate, 930 mg,7.00 mmol) in water (5 mL) dropwise via additional funnel. The ice bathwas removed and the reaction was stirred at room temperature overnight.The reaction was quenched with sodium sulfite. The reaction mixture wasconcentrated under reduced pressure and the resulting residue waspurified by pre-HPLC to give the title compound (60 mg, 47% yield) as awhite solid. MS (ES+) 359.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.12(s, 1H), 11.94-11.93 (m, 1H), 8.07 (d, 2H), 7.92 (s, 1H), 7.62 (s, 1H),7.37 (d, 2H), 7.04 (d, 2H), 4.52 (s, 2H), 2.68 (d, 3H).

Example 83 6-chloro-5-[4-(pyrrolidin-2-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1 tert-butyl2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate

To a suspension of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (150 mg,0.57 mmol) in mixture solvent of 1,4-dioxane/N,N-dimethylformamide (5:1,3 mL) was added vilsmeier salt (165 mg, 1.71 mmol) under nitrogen. Themixture was stirred at room temperature for 30 minutes under nitrogen.Potassium carbonate (2.0 M in water, 1.5 mL) was added and stirred for10 minutes, followed by the addition of tert-butyl2-(4-bromophenyl)pyrrolidine-1-carboxylate (180 mg, 0.55 mmol), themixture was degassed with nitrogen for 10 min., then treated withPd(dppf)Cl₂ (62 mg, 0.086 mmol). The reaction mixture was stirred at 90°C. for 30 minutes. The mixture was filtered through a Celite pad and thefiltrate was partitioned between ethyl acetate (10 mL) and water (20mL). The aqueous phase was extracted two times with ethyl acetate (10mL), the combined organic layers were washed with brine (15 mL), driedover sodium sulfate, filtrated, and concentrated to afford crude productwhich was purified by silica-gel chromatography to give the titlecompound (170 mg, 72.2% yield).

Step 25-{4-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]phenyl}-6-chloro-1H-indole-3-carboxylicacid

The tert-butyl2-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate(160 mg, 0.377 mmol) was dissolved in acetonitrile (9 mL) and warmt-butanol (9 mL) followed by the addition of 2-methyl-2-butene (6.00 mL,56.5 mmol) and cooled to 0° C. followed by the addition of an aqueoussolution of sodium chlorite (763 mg, 11.3 mmol) and sodium phosphate(monobasic and monohydrate, 1.56 g, 11.3 mmol) in water (5 mL) dropwisevia additional funnel. The ice bath was removed and the mixture wasallowed to warm to room temperature. The suspension was stirredovernight. To the suspension was added sodium sulfite (1.43 g, 11.3mmol) in water (3 mL) and the resultant mixture concentrated to removethe organic solvent followed by extraction three times with ethylacetate (15 mL). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated to afford crude product which waspurified by reverse phase HPLC to afford the title compound (140 mg,84.2% yield).

Step 3 6-chloro-5-[4-(pyrrolidin-2-yl)phenyl]-1H-indole-3-carboxylicacid

To a suspension of5-{4-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]phenyl}-6-chloro-1H-indole-3-carboxylicacid (140 mg, 0.318 mmol) in ethyl acetate (10 mL) was added hydrogenchloride in ethyl acetate (4 N HCl in EtOAc, 10 mL) under nitrogen. Thesuspension was stirred for 4.5 hours at room temperature. The mixturewas concentrated to afford the desired product (100 mg, 83.5% yield). MS(ES+) 341 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, 1H), 8.10 (s,1H), 7.95 (s, 1H), 7.66 (s, 1H), 7.62 (d, 2H), 7.52 (d, 2H), 4.60 (s,1H), 3.35 (s, 4H), 2.49 (m, 2H).

Example 846-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-2-yl]phenyl}-1H-indole-3-carboxylicacid

Step 1 2-(4-bromophenyl)pyrrolidine hydrogen chloride

The suspension of tert-butyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate(1.2 g, 3.7 mmol) in anhydrous methanol (10 mL) was added hydrogenchloride in methanol (20 mL, 4.0 M in MeOH) under nitrogen. The reactionwas stirred at room temperature for 1.5 hours. The mixture wasconcentrated to afford the title compound (0.99 g, quantitative yield)which was used without purification in the next step.

Step 2 2-(4-bromophenyl)-1-(methylsulfonyl)pyrrolidine

To a suspension of 2-(4-bromophenyl)pyrrolidine hydrogen chloride (250mg, 0.952 mmol) in anhydrous methylene chloride (5 mL) was addedtriethylamine (0.66 mL, 4.76 mmol) under N₂. The mixture was stirred atroom temperature for 15 min. under N₂. After 15 min., methanesulfonylchloride (0.31 g, 2.72 mmol) was added and the mixture was stirred atroom temperature under N₂ overnight. Additional methanesulfonyl chloride(0.29 g, 2.54 mmol) and triethylamine (0.35 mL, 2.38 mmol) were addedand stirred at room temperature for 4 h. The reaction was concentrated,and to the residue was added water (20 mL) and methylene chloride (18mL), and the organic phase was washed with water (10 mL×3), brine (15mL×1), dried over sodium sulfate and concentrated to afford the desiredproduct (240 mg, 85.2% yield) which was used without furtherpurification in the next step.

Step 36-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-2-yl]phenyl}-1H-indole-3-carbaldehyde

To a suspension of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (210 mg,0.80 mmol) in a solvent mixture of 1,4-dioxane/N,N-dimethylformamide=5:1(3 mL) was added Vilsmer-salt (232 mg, 4.80 mmol) under nitrogen and themixture was stirred at room temperature for 30 minutes. Potassiumcarbonate (2.0 M in water, 2.0 mL) was added to the above suspensionfollowed by the addition of2-(4-bromophenyl)-1-(methylsulfonyl)pyrrolidine (240 mg, 0.79 mmol) in asolvent mixture of 1,4-dioxane/N,N-dimethylformamide=5:1 (3 mL) addedunder nitrogen. The mixture was degassed with nitrogen for 10 minutes.The mixture was treated with Pd(dppf)Cl₂ (87 mg, 0.12 mmol) and stirredat 90° C. under nitrogen for 30 minutes. The mixture was filteredthrough a celite pad and the filtrate was partitioned between ethylacetate (10 mL) and water (20 mL). The aqueous phase was extracted threeadditional times with ethyl acetate (10 mL) and the combined the organicphases were washed with brine (15 mL), dried over sodium sulfate,filtered and concentrated to afford crude which was purified bysilica-gel chromatography to give the title compound (76.7 mg, 24.0%yield).

Step 46-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-2-yl]phenyl}-1H-indole-3-carboxylicacid

To a mixture of6-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-2-yl]phenyl}-1H-indole-3-carbaldehyde(75 mg, 0.19 mmol) in acetonitrile/t-butanol (4.5 mL/4.5 mL) was added2-methyl-2-butene (3.00 mL, 28.2 mmol). The reaction mixture was cooledto 0° C. followed by the addition of an aqueous solution of sodiumchlorite (377 mg, 5.58 mmol) and sodium phosphate (monobasic andmonohydrate, 770 mg, 5.58 mmol) in water (9 mL) dropwise via additionalfunnel. The ice bath was removed and the reaction was stirred at roomtemperature overnight. The following morning, 2-methyl-2-butene (1.50mL, 14.1 mmol) and an aqueous solution of sodium chlorite (125 mg, 1.86mmol) and sodium phosphate (monobasic and monohydrate, 257 mg, 1.86mmol) in water (3 mL) was added in a dropwise manner. The reaction wasallowed to stir overnight at room temperature. The reaction was quenchedwith sodium sulfite (940 mg, 7.44 mmol) in water (3 mL). The reactionmixture was concentrated under reduced pressure to remove the volatileorganics. The aqueous layer was extracted three times with ethylacetate. The combined organic layers were dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified by reverse phase HPLC to give the desired product (40.1 mg,51.2% yield). MS (ES+) 441.0 (M+Na)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95(s, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.40 (m, 4H),4.94-4.91 (m, 1H), 3.51-3.49 (s, 2H), 2.95 (s, 3H), 2.40-2.30 (m, 1H),1.91-1.86 (m, 3H).

Example 856-chloro-5-[4-(1-methylpyrrolidin-2-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1 2-(4-bromophenyl)-1-methylpyrrolidine

To a suspension of 2-(4-bromophenyl)pyrrolidine hydrogen chloride (200mg, 0.76 mmol) in anhydrous MeOH (5 mL) was added formaldehyde (114 mg,3.80 mmol) under N₂. The mixture was stirred at room temperature for 2 hunder N₂. After 2 h, NaBH(OAc)₃ (242 mg, 1.14 mmol) was added and themixture was stirred at room temperature under N₂ overnight. Additionalformaldehyde (2 mL) and NaBH(OAc)₃ (242 mg, 1.14 mmol) were then addedand the mixture was stirred at room temperature for 5 hrs. The reactionwas concentrated and water was added (20 mL) with dichloromethane (8mL). The layers were separated and the water was extracted withdichloromethane (8 mL×3). The organic layers were combined, washed withbrine, dried over sodium sulfate, and concentrated to afford the titlecompound (0.203 g, quantitative yield) which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (d, 2H), 7.28 (d, 2H),3.15-3.10 (t, 1H), 3.04-3.00 (t, 1H), 2.22-2.18 (q, 1H), 2.13-2.09 (m,1H), 2.05 (s, 3H), 1.80-1.65 (m, 2H), 1.53-1.50 (m, 1H).

Step 26-chloro-5-[4-(1-methylpyrrolidin-2-yl)phenyl]-1H-indole-3-carbaldehyde

To a suspension of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (290 mg,1.10 mmol) in mixture of 1,4-dioxane/N,N-dimethylformamide=5:1 (3 mL)was added Vilsmer-salt (330 mg, 3.30 mmol) under nitrogen and stirred atroom temperature for 30 minutes. Potassium carbonate (2.0 M in water,2.9 mL) was added to the above suspension followed by the addition of2-(4-bromophenyl)-1-methylpyrrolidine (200 mg, 0.84 mmol) in a mixtureof 1,4-dioxane/N,N-dimethylformamide=5:1 (3 mL). The mixture wasdegassed with nitrogen for 10 minutes. The mixture was then treated withPd(dppf)Cl₂ (125 mg, 0.165 mmol). The mixture was stirred at 90° C.under nitrogen for 30 minutes. The mixture was filtered through a celitepad and the filtrate was partitioned between ethyl acetate (10 mL) andwater (20 mL), the aqueous phase was extracted three additional timeswith ethyl acetate (10 mL) and the combined organic phases were washedwith brine (15 mL), dried over sodium sulfate, filtered and concentratedto afford crude product which was purified by silica-gel chromatographyto afford the title compound (150 mg, 53.2% yield).

Step 36-chloro-5-[4-(1-methylpyrrolidin-2-yl)phenyl]-1H-indole-3-carboxylicacid

To a mixture of6-chloro-5-[4-(1-methylpyrrolidin-2-yl)phenyl]-1H-indole-3-carbaldehyde

(150 mg, 0.443 mmol) in acetonitrile/t-butanol (9 mL/9 mL) was added2-methyl-2-butene (7.50 mL, 28.2 mmol). The reaction mixture was cooledto 0° C. followed by the addition of an aqueous solution of sodiumchlorite (598 mg, 8.86 mmol) and sodium phosphate (monobasic andmonohydrate, 1220 mg, 8.860 mmol) in water (9 mL) dropwise via syringe.The ice bath was removed and the reaction was stirred at roomtemperature overnight. The reaction was quenched with sodium sulfite(1.12 g, 8.86 mmol) in water (3 mL). The reaction mixture wasconcentrated under reduced pressure to remove the volatile organics. Theaqueous layer was extracted three times with ethyl acetate. The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby reverse phase HPLC to give the title compound (10 mg, 5.0% yield). MS(ES+) 355.0 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.11 (s, 1H), 7.97 (s,1H), 7.59-7.58 (m, 5H), 4.19 (m, 1H), 3.74-3.71 (m, 1H), 3.17-3.14 (m,1H), 2.70 (s, 3H), 2.55-2.52 (m, 1H), 2.33-2.21 (m, 1H), 2.28-2.21 (m,3H).

Example 866-chloro-5-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carboxylicacid

Step 16-chloro-5-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde

A mixture of 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole(100 mg, 0.38 mmol) and N,N-dimethylformiminium chloride (97 mg, 0.76mmol) in DMF (3 mL) and dioxane (0.6 mL) was stirred at room temperaturefor 30 min. Potassium carbonate (2 mL, 4 mmol, 2 N) was added to themixture. Then 2-(4-bromo-3-fluorophenoxy)ethanol (96 mg, 0.38 mmol) andPd(dppf)Cl₂ (20 mg, 0.03 mmol) was added to the reaction. The mixturewas degassed by passing nitrogen through the solution for 5 min. andstirred at 80° C. for 2 hrs. The reaction was cooled and concentrated.The residue was dissolved by EtOAc (100 mL), washed with water (30 mL),saturated NH₄Cl (30 mL), brine (30 mL), dried over sodium sulfate andconcentrated to afford a crude product. The crude was further purifiedby silica gel chromatography (PE/EtOAc=20% to 50%) to give the titlecompound (40 mg, 31% yield) as a light yellow oil.

¹H NMR (400 MHz, CD₃OD) δ 9.91 (s, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.63(s, 1H), 7.28 (t, 1H), 6.86 (dd, 1H), 6.80 (dd, 1H), 4.12 (t, 2H), 3.92(t, 2H).

Step 26-chloro-5-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carboxylicacid

To a solution of6-chloro-5-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde(40 mg, 0.12 mmol) in water (1 mL) and t-butanol (1 mL) was added sodiumchlorite (210 mg, 2.30 mmol), 2-methyl-2-butene (0.5 mL) and sodiumdihydrogen phosphate (350 mg, 2.30 mmol). The reaction solution wasstirred at room temperature for 10 hrs. The reaction was diluted withwater (5 mL) and extracted with dichloromethane (20 mL×3). The combinedorganic phase was washed with water (20 mL), brine (20 mL) dried oversodium sulfate and concentrated to give a crude product. The crude waspurified by reverse phase HPLC to give the title compound (14 mg, 59%yield) as an off-white solid. MS (ES−) 348.1 (M−H)⁻. ¹H NMR (400 MHz,CD₃OD) δ 8.04 (s, 2H), 7.63 (s, 1H), 7.28 (s, 1H), 6.91 (dd, 2H), 6.86(dd, 2H), 4.16 (t, 2H), 3.96 (t, 2H).

Example 876-chloro-5-[(2R)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1H-indole-3-carboxylicacid

Step 16-chloro-5-[(2R)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1H-indole-3-carbaldehyde

A mixture of [(2R)-6-bromo-2,3-dihydro-1,4-benzodioxin-2-yl]methanol(0.54 g, 2.05 mmol) (which can be prepared as in Biorg. Med. Chem. 2007,15, 4048.), 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole(0.52 g, 4.06 mmol) in DMF (4 mL) and dioxane (4 mL) was stirred at roomtemperature for 30 min. under N₂. Pd(dppf)Cl₂ (100 mg, 0.137 mmol) and 2N potassium carbonate (10 mL, 20 mmol) was added. The resulting mixturewas stirred for 30 min. at 90° C. under N₂. TLC showed the reaction wascomplete. Water (50 mL) and methylene chloride (50 mL) was added. Theaqueous layer was extracted with methylene chloride (30 mL×3). Thecombined organic layer was dried over sodium sulfate, filtered andevaporated to give the title compound (1 g) which was used in the nextstep without further purification.

Step 26-chloro-5-[(2R)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1H-indole-3-carboxylicacid

A mixture of6-chloro-5-[(2R)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1H-indole-3-carbaldehyde(1.0 g, 2.9 mmol), sodium chlorite (5.28 g, 58.3 mmol), sodiumdihydrogen phosphate (9.06 g, 58.1 mmol) in 2-methyl-2-butene (10 mL),water (10 mL), t-butanol (10 mL) and acetonitrile (10 mL) was stirredovernight at room temperature. The mixture was quenched with saturatedaqueous sodium bisulfite. Water (50 mL) and methylene chloride (50 mL)was added. The aqueous layer was extracted with methylene chloride (50mL×3). The combined organic layer was dried over sodium sulfate,filtered and evaporated to give residue which was purified by reversephase HPLC to give the title compound (105 mg, 14.3% yield).

MS (AP+) 360.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.99 (s, 1H), 7.98 (s,1H), 7.54 (s, 1H), 6.90-6.93 (m, 3H), 4.36 (dd, 1H), 4.22-4.24 (m, 1H),4.09 (dd, 1H), 3.79-3.81 (m, 2H).

Example 885-[4-(1-carboxycyclopropyl)phenyl]-6-chloro-1H-indole-3-carboxylic acid

Step 1 1-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]cyclopropanecarboxylic acid

To a solution of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (152 mg,0.577 mmol) in anhydrous dioxane (5 mL) and DMF (1 mL) was addedN,N-dimethylformiminium chloride (170 mg, 1.33 mmol). The reactionmixture was stirred at room temperature for 20 mins. A thick solutionwas observed after 20 mins. 2 N potassium carbonate (400 mg, 2.90 mmol),1-(4-bromophenyl)cyclopropanecarboxylic acid (137 mg, 0.568 mmol) andPd(dppf)Cl₂ (50 mg, 0.068 mmol) were then added. The reaction wasdegassed with N₂ for 2 minutes. The reaction was then heated to 90° C.for 30 minutes. The mixture was poured into water (60 mL) and the layersseparated. The aqueous layer was extracted with ethyl acetate (50 mL×2).The aqueous phase was acidified to pH=5 with 1 N HCl and then extractedwith ethyl acetate (50 mL×3). The combined organic phases were washedwith brine (50 mL), dried and concentrated to give the title compound(253 mg, quantitative yield) as a brown oil, which was used in the nextstep without further purification.

Step 25-[4-(1-carboxycyclopropyl)phenyl]-6-chloro-1H-indole-3-carboxylic acid

1-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]cyclopropanecarboxylic acid(253 mg, 0.577 mmol) was dissolved in MeCN (6 mL) and warm t-butanol (6mL). 2-methyl-2-butene (4 mL) was added and the mixture was cooled to 0°C. Sodium chlorite (780 mg, 11.6 mmol) and sodium dihydrogen phosphatedihydrate (1800 mg, 11.54 mmol) were dissolved in water (4 mL). Theaqueous solution was added to the organic solution dropwise via additionfunnel and the ice bath was removed and the mixture was allowed to warmto room temperature overnight. The reaction was concentrated to removethe organics and extracted with ethyl acetate (20 mL×3). The combinedorganics were washed with brine (20 mL), dried and concentrated and thenpurified by reverse phase HPLC to give the title compound (62.4 mg,30.5% yield) as a white solid. MS (AP+) 377.9 (M+Na)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.02 (s, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 7.40 (m, 4H), 1.61(m, 2H), 1.27 (m, 2H).

Example 896-chloro-5-[4-(oxetan-3-ylmethoxy)phenyl]-1H-indole-3-carboxylic acid

Step 1 3-[(4-bromophenoxy)methyl]oxetane

To a solution of oxetan-3-ylmethanol (1.00 g, 11.3 mmol) in DMF (10 mL)was added NaH (300 mg, 13.6 mmol) at 0° C. The mixture was then stirredat 0° C. for 10 min. 1-Bromo-4-fluorobenzene (2.30 g, 13.6 mmol) wasadded to the solution. The mixture was stirred at 90° C. for 2 h. Themixture was partitioned between water and EtOAc (30 mL×3). The combinedorganics was dried and concentrated to give the title compound (420 mg,15% yield) as a yellow oil.

Step 26-chloro-5-[4-(oxetan-3-ylmethoxy)phenyl]-1H-indole-3-carbaldehyde

To a sealed tube was added6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (100 mg,0.38 mmol) and N,N-dimethylformiminium chloride (97.7 mg, 0.76 mmol) indioxane/DMF=5/1 (6 mL). The sealed vial was stirred at room temperaturefor 10 min. to give a white slurry. To the slurry was added 2 Mpotassium carbonate (1.0 mL, 1.9 mmol),3-[(4-bromophenoxy)methyl]oxetane (92.3 mg, 0.38 mmol) and Pd(dppf)Cl₂(30 mg, 0.05 mmol). The sealed vial was heated to 90° C. for 30 min. TLC(petroleum ether/ethyl acetate=1:1) showed the reaction was complete.The reaction was quenched with water (20 mL), then washed with EtOAc (20mL×3). The combined organics was dried over sodium sulfate, filtered,concentrated, and purified by combi-flash to give the title compound (70mg, 53% yield) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 9.90 (s,1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.62 (s, 1H), 7.38 (d, 2H) 7.03 (d,2H), 4.92 (m, 2H), 4.65 (t, 1H), 4.61 (s, 1H), 4.28-4.27 (m, 2H), 3.50(m, 1H).

Step 3 6-chloro-5-[4-(oxetan-3-ylmethoxy)phenyl]-1H-indole-3-carboxylicacid

To a mixture of6-chloro-5-[4-(oxetan-3-ylmethoxy)phenyl]-1H-indole-3-carbaldehyde (70mg, 0.2 mmol) in acetonitrile/t-butanol=1/1 (5 mL) was added2-methyl-2-butene (0.5 mL). The reaction was cooled to 0° C. and anaqueous solution of sodium chlorite (180 mg, 2.00 mmol) and sodiumdihydrogen phosphate (270 mg, 6.00 mmol) in water (0.5 mL) were addeddropwise via additional funnel. Then ice bath was removed, the reactionwas stirred at room temperature for 12 h. The reaction was quenched withsodium sulfite. The mixture was partitioned between EtOAc (20 mL×3) andwater. The combined organics was concentrated to give a residue, whichwas purified by reverse phase HPLC to give the title compound (25 mg,35% yield) as an off-white solid. MS (AP+) 358.1 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.95 (s, 1H), 7.61 (s, 1H), 7.35 (d, 2H),7.04 (d, 2H), 4.74 (t, 2H), 4.46 (t, 2H), 4.26 (t, 2H), 3.44-3.42 (m,1H).

Example 90 5-[4-(2-carboxyethoxy)phenyl]-6-chloro-1H-indole-3-carboxylicacid

Step 1 3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenoxy]propanoic acid

To a solution of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (150 mg,0.57 mmol) in dioxane (5 mL) and DMF (1 mL) was addedN,N-dimethylformiminium chloride (155 mg, 1.21 mmol). The reactionmixture was stirred at room temperature for 20 min. 2 N potassiumcarbonate (314 mg, 2.28 mmol), 3-(4-bromophenoxy)propanoic acid (139 mg,0.57 mmol) and Pd(dppf)Cl₂ (21 mg, 0.028 mmol) were then added. Thereaction was degassed with N₂ and heated to 90° C. for 30 min. Thereaction was extracted with ethyl acetate (10 mL×2). The organic layerswere washed with brine (10 mL), dried over sodium sulfate, andconcentrated to give the title compound (170 mg, 87% yield) as a brownoil.

Step 2 5-[4-(2-carboxyethoxy)phenyl]-6-chloro-1H-indole-3-carboxylicacid

To a solution of 3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]propanoicacid (170 mg, 0.496 mmol) in acetonitrile (7.7 mL), t-butanol (7.7 mL)and 2-methyl-2-butene (7.0 mL) was added a solution of sodium chlorite(668 mg, 9.91 mmol) and sodium dihydrogen phosphate (1.37 g, 9.91 mmol)in water (7.7 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 18 h. The reaction was quenched with a solution ofsodium sulfite (1.37 mg, 10.9 mmol) in water (5.0 mL), and extractedwith ethyl acetate (30 mL×2). The organic layers were washed with brine(30 mL) and dried over sodium sulfate, filtered and concentrated to givea crude product, which was purified by reverse phase HPLC to give thetitle compound (34 mg, 19% yield) as a white solid. MS (AP−) 358.1(M−1)⁻. ¹H NMR (400 MHz, CD₃OD) δ 8.01 (s, 1H), 7.99 (s, 1H), 7.55 (s,1H), 7.36 (d, 2H), 6.99 (d, 2H), 4.30 (t, 2H), 2.79 (t, 2H).

Example 91 5-[4-(azetidin-3-yl)phenyl]-6-chloro-1H-indole-3-carboxylicacid

Step 1

5-[4-(azetidin-3-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde

To a solution of6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (80 mg, 0.30mmol) in dioxane (2 mL) was added Vilsmeier salt (150 mg, mmol) and DMF(0.1 mL). The resulting mixture was stirred at room temperature for 20min. The reaction was quenched with 2 N K₂CO₃ (1.5 mL, 3.0 mmol).3-(4-Bromophenyl)azetidine (64 mg, 0.30 mmol) and Pd(dppf)Cl₂ (20 mg,0.030 mmol) were next added, and then heated to 90° C. for 30 min. Thereaction mixture was extracted with ethyl acetate (3 mL×3). The combinedorganic layers were concentrated in vacuo to afford the title compound(94 mg, quantitative yield), which was used directly for the next stepwithout further purification.

Step 2 5-[4-(azetidin-3-yl)phenyl]-6-chloro-1H-indole-3-carboxylic acid

To 5-[4-(azetidin-3-yl)phenyl]-6-chloro-1H-indole-3-carbaldehyde (94 mg,0.30 mmol) in 2-methyl-2-butene/t-BuOH/H2O (v/v/v=1/1/1, 4 mL) was addedsodium dihydrogen phosphate (364 mg, 3.04 mmol) and sodium chlorite (274mg, 3.04 mmol) at room temperature. The resulting mixture was stirred atroom temperature for 24 hours. To the reaction mixture was added sodiumsulfite (383 mg, 3.04 mmol), then concentrated in vacuo and purified viareverse phase HPLC to give the title compound (10 mg, 10% yield). ¹H NMR(400 MHz, CD₃OD) δ 8.03-80.4 (d, 2H), 7.62 (s, 1H), 7.48-7.52 (m, 4H),4.44-4.48 (m, 2H), 4.32-4.34 (m, 3H).

Example 92 6-chloro-5-(5-phenylpyrazin-2-yl)-1H-indole-3-carboxylic acid

Step 1 6-chloro-5-(5-phenylpyrazin-2-yl)-1H-indole-3-carbaldehyde

To a 0.4 M solution of chloromethylene dimethylammonium chloride in DMF(7.5 mL, 3.8 mmol) was added6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (493 mg,1.88 mmol). The mixture was stirred at 30° C. for 2 hrs. 0.50 mL of thissolution (0.15 mmol) was placed in a vial with a 0.3 M solution of2-chloro-5-phenylpyrazine in DMF (0.50 mL, 0.15 mmol). 2 M potassiumcarbonate (0.30 mL, 0.60 mmol) was then added and the mixture purgedwith nitrogen. PddppfCl₂ (9 mg, 0.01 mmol) was then added and the vialcapped and heated to 90° C. for 3 hours. The reaction mixture wasconcentrated by Speedvac and purified via preparative TLC to give thetitle compound that was taken forward without further purification.

Step 2 6-chloro-5-(5-phenylpyrazin-2-yl)-1H-indole-3-carboxylic acid

A solution of 2.5 M/2.65 M of sodium chlorite/sodium dihydrogenphosphate in water was prepared and 1.0 mL (2.5 mmol sodium chlorite and2.6 mmol sodium dihydrogen phosphate) was added to a vial containing6-chloro-5-(5-phenylpyrazin-2-yl)-1H-indole-3-carbaldehyde, 1.0 mL THF,0.5 mL t-butanol, 0.5 mL 2-methyl-2-butene, and sealed then heated to30° C. for 3 hours. Sodium sulfite (315 mg, 2.50 mmol) was then addedand the mixture stirred for 15 min. Ethyl acetate was then added toextract (3×1 mL). The organic layer was separated and solvents removedby speedvac. The residue was purified by reverse phase HPLC to give thetitle compound. MS(AP−) 348 (M−H)⁻. RT=2.093 Column Xbridge C18 2.1×50mm 5 μm, Temperature 50° C. Mobile Phase A=0.05% NH4OH in water. MobilePhase B=100% acetonitrile. Gradient: Initial 5% B Time 0.00 mins, 5% BTime 0.50 mins, 5% B Time 3.40 mins, 100% B Time 4.20 mins, 100% B Time4.21 mins, 5% B Time 4.70 mins, 5% B Flow rate, 0.8 mL/min Injectionvolume 2 μL. Agilent 1200 HPLC/1956 MSD/SEDEX 75 ELSD Ionization ModeAPI-ES Polarity Negative.

Example 936-chloro-5-[4-(2-hydroxyethyl)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

Step 16-chloro-5-[4-(2-hydroxyethyl)-3-methoxyphenyl]-1H-indole-3-carbaldehyde

To a 0.4 M solution of chloromethylene dimethylammonium chloride in DMF(7.5 mL, 3.8 mmol) was added6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole (493 mg,1.88 mmol). The mixture was stirred at 30° C. for 2 hrs. 0.50 mL of thissolution (0.15 mmol) was placed in a vial with a 0.3 M solution of2-(4-bromo-2-methoxyphenyl)ethanol in DMF (0.50 mL, 0.15 mmol). 2 Mpotassium carbonate (0.30 mL, 0.60 mmol) was then added and the mixturewas purged with nitrogen. PddppfCl₂ (9 mg, 0.01 mmol) was then added andthe vial capped and heated to 90° C. for 3 hours. The reaction mixturewas concentrated by Speedvac and purified via preparative TLC to givethe title compound that was taken forward without further purification.

Step 26-chloro-5-[4-(2-hydroxyethyl)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

A solution of 2.5 M/2.65 M of sodium chlorite/sodium dihydrogenphosphate in water was prepared and 1.0 mL (2.5 mmol sodium chlorite and2.6 mmol sodium dihydrogen phosphate) was added to a vial containing6-chloro-5-[4-(2-hydroxyethyl)-3-methoxyphenyl]-1H-indole-3-carbaldehyde,1.0 mL THF, 0.5 mL t-butanol, 0.5 mL 2-methyl-2-butene, and sealed thenheated to 30° C. for 3 hours. Sodium sulfite (315 mg, 2.50 mmol) wasthen added and the mixture stirred for 15 min. Ethyl acetate was thenadded to extract (3×1 mL). The organic layer was separated and solventsremoved by speedvac. The residue was purified by reverse phase HPLC togive the title compound. MS(AP−) 344 (M−H)⁻. Retention time=1.892 ColumnXbridge C18 2.1×50 mm 5 μm, Temperature 50° C. Mobile Phase A=0.05%NH4OH in water. Mobile Phase B=100% acetonitrile. Gradient: Initial 5% BTime 0.00 mins, 5% B Time 0.50 mins, 5% B Time 3.40 mins, 100% B Time4.20 mins, 100% B Time 4.21 mins, 5% B Time 4.70 mins, 5% B Flow rate,0.8 mL/min Injection volume 2 μL. Agilent 1200 HPLC/1956 MSD/SEDEX 75ELSD Ionization Mode API-ES Polarity Negative

Example 946-chloro-5-[4-(pyridin-3-ylmethoxy)phenyl]-1H-indole-3-carboxylic acid

Step 1 1-tert-butyl 3-methyl5-bromo-6-chloro-1H-indole-1,3-dicarboxylate

A solution of methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (756 mg,2.62 mmol) in anhydrous tetrahydrofuran (13 mL) was treated withdi-tert-butyl dicarbonate (686 mg, 3.14 mmol) and DMAP (30 mg, 0.26mmol). The reaction was stirred at room temperature for two hours, andwas then partitioned between ethyl acetate and water. The organic layerwas separated, washed with brine, and dried over sodium sulfate. Themixture was filtered and concentrated in vacuo to give a pink, oilysolid. This material was triturated with a mixture of ethyl acetate andheptane (1:3), and the resulting solids were collected by filtration.The solids were then washed with heptane and dried in vacuo to give alight pink solid (320 mg). The filtrate was concentrated in vacuo, andthe resulting material triturated as above to get a second batch ofproduct (380 mg). The two batches were combined to give the titlecompound (700 mg, 68% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.30 (s, 1H),8.27 (m, 2H), 3.88 (s, 3H), 1.65 (s, 9H).

Step 2 1-tert-butyl 3-methyl6-chloro-5-(4-hydroxyphenyl)-1H-indole-1,3-dicarboxylate

A mixture of 1-tert-butyl 3-methyl5-bromo-6-chloro-1H-indole-1,3-dicarboxylate (300 mg, 0.78 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (255 mg, 1.16mmol), 1,4-dioxane (4.2 mL) and aqueous potassium phosphate tribasic(4.6 mL, 0.5 M, 2.3 mmol) was treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (57 mg, 0.78mmol). The pink mixture was evacuated and refilled with nitrogen threetimes. The sealed reaction was heated at 85° C. for 10 minutes. Thecooled reaction mixture was filtered through Celite, and the filter padwas washed with water followed by three washes with ethyl acetate. Thefiltrate layers were separated, and the aqueous layer was extractedagain with ethyl acetate. The organic extracts were combined, washedwith brine and then dried over sodium sulfate. The mixture was filteredand concentrated in vacuo to give an oily solid which was purified byflash chromatography eluting with heptanes/ethyl acetate (90:10 to40:60) to give the title compound (279 mg, 89% yield) as a white solid.MS (ES+) 302 (M-Boc+1)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.26(s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.26 (d, J=8.29 Hz, 2H), 6.86 (d,J=8.54 Hz, 2H), 3.32 (s, 3H), 1.66 (s, 9H).

Step 3 1-tert-butyl 3-methyl6-chloro-5-[4-(pyridin-3-ylmethoxy)phenyl]-1H-indole-1,3-dicarboxylate

A mixture of 1-tert-butyl 3-methyl6-chloro-5-(4-hydroxyphenyl)-1H-indole-1,3-dicarboxylate (30 mg, 0.075mmol), polymer supported triphenylphosphine (50 mg, 0.15 mmol),anhydrous tetrahydrofuran (1.0 mL), pyridin-3-ylmethanol (0.015 mL, 0.15mmol), and bis(2-methoxyethyl)-diazene-1,2-dicarboxylate) (35 mg, 0.15mmol) was sealed in a vial and stirred vigorously at 70° C. for 18hours. The cooled reaction mixture was filtered through a pad of Celite,and the filter pad was washed with diethyl ether twice. The filtrate wasconcentrated in vacuo, and the residue partitioned between diethyl etherand water. The organic layer was separated and washed sequentially withwater and then brine. The ether layer was concentrated in vacuo and togive the title compound, which was used directly in the next step. MS(ES+) 493 (M+1)⁺.

Step 4 6-chloro-5-[4-(pyridin-3-ylmethoxy)phenyl]-1H-indole-3-carboxylicacid

A mixture of crude 1-tert-butyl 3-methyl6-chloro-5-[4-(pyridin-3-ylmethoxy)phenyl]-1H-indole-1,3-dicarboxylate(37 mg, 0.075 mmol), methanol (0.8 mL) and 1M aqueous sodium hydroxide(0.45 mL, 0.45 mmol) was sealed in a vial and heated at 75° C. for 17hours, causing a solution to form. After cooling to room temperature,the reaction mixture was concentrated via a stream of nitrogen, anddiluted with ethyl acetate and saturated aqueous citric acid slowly. Thelayers were separated, and the aqueous layer was extracted two timeswith ethyl acetate. The organic layers were combined, concentrated invacuo, and the resulting clear oil was dissolved in DMSO (0.9 mL) andpurified via reverse phase prep-HPLC to give the title compound (6.4 mg,23% over two steps). MS (ES+) 379.1 (M+H)⁺. Retention time: 2.28 min.Column: Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%.Gradient: 95% H₂O/5% MeCN linear to 5% H₂O/95% MeCN over 4.0 min, HOLDat 5% H₂O/95% MeCN to 5.0 min. Flow: 2.0 mL/min.

Example 95 6-cyano-5-[4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carboxylicacid

3-formyl-5-[4-(2-hydroxyethoxy)phenyl]-1H-indole-6-carbonitrile

A mixture of 5-bromo-3-formyl-1H-indole-6-carbonitrile (100 mg, 0.401mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (150 mg, 0.439mmol), and oven-dried potassium acetate (177 mg, 1.80 mmol) in1,4-dioxane (2 mL) was degassed with nitrogen for 10 minutes, thentreated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(29.3 mg, 0.040 mmol) and heated to 110° C. in an oil bath for 3.5hours. The cooled reaction mixture was filtered through a plug of celiteeluting with ethyl acetate (45 mL). The filtrate was evaporated in vacuoto give a black solid (160 mg), and the crude product was partiallydissolved in toluene (1.5 mL). A microwave vial was charged with thestock solution in toluene prepared above (0.75 mL, assume 0.2 mmol),2-(4-bromophenoxy)ethanol (54 mg, 0.25 mmol), ethanol (0.37 mL), and 2Maqueous potassium carbonate (0.4 mL, 0.8 mmol). The mixture was degassedwith nitrogen for 10 minutes, then treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.9 mg,0.019 mmol). The reaction mixture was heated at 90° C. for two hours.The cooled reaction mixture was poured into saturated aqueous ammoniumchloride (15 mL). The product was extracted with ethyl acetate (4×10 mL)and the combined organic layers were dried over sodium sulfate, filteredand evaporated in vacuo to give the title compound as an amber oil (110mg). MS (ES−) 305.2 (M−H)⁻.

Step 2 6-cyano-5-[4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carboxylic acid

To a solution of crude3-formyl-5-[4-(2-hydroxyethoxy)phenyl]-1H-indole-6-carbonitrile (110 mg,assume 0.2 mmol) in a mixture of THF (1.5 mL) and tert-butanol (1.5 mL)was added 2-methyl-2-butene (0.638 mL, 6.0 mmol) followed by a solutionof sodium chlorite (169 mg, 2.0 mmol) and sodium phosphate monobasicmonohydrate (284 mg, 2.06 mmol) in water (1.1 mL) via glass pipet atroom temperature. The mixture was stirred at room temperature for 15.5hours. The reaction mixture was poured into saturated aqueous ammoniumchloride solution (10 mL) and extracted with ethyl acetate (3×8 mL). Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo. The residue was dissolved in DMSO (1.8 mL) and half of thissolution was purified by reverse phase prep-HPLC to give the titlecompound (5 mg). MS (ES−) 321.1 (M−H)⁻. Retention time: 0.90 min WatersXbridge dC18 5 um 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCNover 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH₄OH). Flow:2.0 mL/min.

Example 966-chloro-5-{4-[3-(hydroxymethyl)oxetan-3-yl]phenyl}-1H-indole-3-carboxylicacid

Step 1 2-benzyloxymethyl-2-(4-bromo-phenyl)-malonic acid diethyl ester

To a room temperature suspension of sodium hydride (210 mg, 5.26 mmol)in N,N-dimethylacetamide (5 mL) was added diethyl 4-bromophenylmalonate(2.03 g, 6.13 mmol) dropwise. Once bubbling had ceased, benzylchloromethyl ether (700 mg, 4.4 mmol) was added. The reaction mixturewas heated to 100° C. for 5 hours, then diluted with ethyl acetate (200mL), washed with water and saturated brine (1×50 mL each), dried overmagnesium sulfate, filtered and concentrated in vacuo to afford 2.45 gyellow oil. The crude material was purified by flash chromatography (80g silica, 0-20% ethyl acetate/heptane, 8 column volumes). Productfractions were combined and concentrated in vacuo to afford the titlecompound as a colorless oil (1.7 g, 89% yield). MS (ES+) 457/459(M+H+Na)⁺; ¹H NMR (500 MHz, CDCl₃) δ ppm 7.45-7.53 (m, 2H), 7.25-7.37(m, 7H), 4.57 (s, 2H), 4.21-4.28 (m, 4H), 4.19 (s, 2H), 1.20-1.31 (m,6H).

Step 2 2-benzyloxymethyl-2-(4-bromo-phenyl)-propane-1,3-diol

To a 0° C. suspension of LAH (444 mg, 11.1 mmol) in diethyl ether (10mL) was added a solution of 2-Benzyloxymethyl-2-(4-bromo-phenyl)-malonicacid diethyl ester (1.67 g, 3.84 mmol) in diethyl ether (10 mL) dropwisevia addition funnel. The reaction mixture was warmed to room temperatureand stirred for 22 hours. The reaction was quenched with water (1.5 mL),15% NaOH (1.5 mL), and water (3 mL) added sequentially. The white slurrywas stirred for 30 minutes, diluted with ethyl acetate and filtered toremove the aluminum salts. The filtrate was concentrated in vacuo toafford a green semisolid, which was purified by flash chromatography (40g silica, 30-82% ethyl acetate/heptane, 10 column volumes). Productfractions were combined and concentrated in vacuo to afford the titlecompound as a colorless oil (482 mg, 36% yield). ¹H NMR (500 MHz, CD₃OD)δ ppm 7.45 (d, J=8.54 Hz, 2H), 7.35 (d, J=8.78 Hz, 2H), 7.22-7.33 (m,5H), 4.51 (s, 2H), 3.92 (s, 4H), 3.82 (s, 2H).

Step 3 3-benzyloxymethyl-3-(4-bromo-phenyl)-oxetane

To a solution of 2-Benzyloxymethyl-2-(4-bromo-phenyl)-propane-1,3-diol(475 mg, 1.35 mmol) in THF (5 mL) at 0° C. was added nBuLi (0.54 mL,2.5M in hexanes, 1.35 mmol). The reaction mixture was stirred for 30minutes at 0° C., at which point a solution of p-toluenesulfonylchloride (258 mg, 1.35 mmol) in THF (5 mL) was added via syringe. Thereaction mixture was stirred for 1 hour at 0° C. and nBuLi (0.54 mL,2.5M in hexanes, 1.35 mmol) was added. The reaction mixture was stirredat 60° C. for 16 hours. The reaction mixture was cooled to roomtemperature, diluted with ethyl ether (100 mL) and washed with water (50mL). The aqueous layer was extracted with ethyl ether (2×50 mL). Thecombined organics were dried over magnesium sulfate, filtered andconcentrated in vacuo to afford 477 mg cloudy beige oil. The crude oilwas purified by flash chromatography (12 g silica, 0-50% ethylacetate/heptane, 26 column volumes). Product fractions were combined andconcentrated in vacuo to afford the title compound as a colorless oil(258 mg, 57% yield).

Step 4 methyl5-[4-(3-benzyloxymethyl-oxetan-3-yl)-phenyl]-6-chloro-1H-indole-3-carboxylate

A mixture of methyl6-Chloro-5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-1H-indole-3-carboxylate(241 mg, 0.75 mmol), 3-Benzyloxymethyl-3-(4-bromo-phenyl)-oxetane (250mg, 0.75 mmol), 2M aqueous potassium carbonate (1.51 mL, 3 mmol),toluene (9 mL), and ethanol (3 mL) was sparged with N2 for 10 minutes,then treated with[1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (29 mg, 0.035 mmol). The reaction mixture washeated to 100 degrees and stirred. After 2 hours the reaction was cooledto room temperature, diluted with ethyl acetate, washed with water andsaturated brine, dried over magnesium sulfate, filtered and concentratedin vacuo to afford a brown oil, which was purified by flashchromatography (40 g silica, 10-60% ethyl acetate/heptane, 17 columnvolumes). Product fractions were combined and concentrated in vacuo toafford the title compound as a colorless solid (215 mg, 62% yield). MS(ES+) 462 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD) δ ppm 8.04 (s, 1H), 8.02 (s,1H), 7.99 (s, 1H), 7.43-7.57 (m, 4H), 7.23-7.34 (m, 5H), 4.90-5.01 (m,4H), 4.58 (s, 2H), 3.90 (s, 3H), 3.88 (s, 2H).

Step 5 methyl6-chloro-5-[4-(3-hydroxymethyl-oxetan-3-yl)-phenyl]-1H-indole-3-carboxylate

To a 0° C. slurry of methyl5-[4-(3-Benzyloxymethyl-oxetan-3-yl)-phenyl]-6-chloro-1H-indole-3-carboxylate(200 mg, 0.433 mmol) in DCM (5 mL) was added boron trichloride (1.73 mL,1.0 M in DCM, 1.73 mmol) via syringe, and the mixture was allowed towarm to room temperature over five hours. The reaction mixture wasconcentrated to dryness, diluted with ethyl acetate (200 mL), washedwith water (10 mL) and saturated brine (10 mL), dried over magnesiumsulfate, filtered and concentrated in vacuo to afford an orange film,which was purified by flash chromatography (12 g silica, 20-100% ethylacetate/heptane, 38 column volumes). Product fractions were combined andconcentrated in vacuo to afford the title compound as a colorless oil(40 mg, 25% yield). MS (ES+) 372 (M+H)⁺; ¹H NMR (500 MHz, CD₃OD) δ ppm8.00-8.04 (m, 2H), 7.60 (s, 1H), 7.44-7.55 (m, 4H), 4.10 (s, 2H),3.95-4.07 (m, 4H), 3.88 (s, 3H).

Step 66-chloro-5-[4-(3-hydroxymethyl-oxetan-3-yl)-phenyl]-1H-indole-3-carboxylicacid

Methyl6-Chloro-5-[4-(3-hydroxymethyl-oxetan-3-yl)-phenyl]-1H-indole-3-carboxylate(40 mg, 0.11 mmol) was dissolved in methanol (3 mL) and 1N aqueoussodium hydroxide (1 mL, 1 mmol), and the mixture was stirred at 70° C.for 24 hours. The mixture was cooled to room temperature and treatedwith saturated ammonium chloride (0.5 mL) and concentrated in vacuo toafford 39 mg colorless solid, which was purified by reversed-phase HPLCto afford the title compound (5 mg, 12% yield). MS (ES−) 356.1183(M−H)⁻. retention time=1.10 min; Column: Waters Atlantis dC18 4.6×50 mm,5 um; Modifier: TFA 0.05%; Gradient: 95% H2O/5% MeCN linear to 5%H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min; Flow: 2.0mL/min.

Example 97 6-Chloro-5-(4-methoxyphenyl)-1H-indazole-3-carboxylic acid

To a solution of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (2.0 g,7.3 mmol), 4-methoxyphenyl boronic acid (1.13 g, 7.40 mmol) in EtOH (50mL) and toluene (50 mL) was added 2 N aqueous potassium carbonatesolution (21.8 mL, 43.6 mmol). The reaction mixture was degassed with N₂for 5 minutes, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (296 mg,0.36 mmol) and degassed with N₂ for an additional 5 minutes. Thereaction mixture was sealed in a pressure tube and heated to 130° C. for3 hours. As the reaction progressed, the suspension became clear andturned to orange then dark brown. The reaction mixture was cooled toroom temperature, and filtered through Celite®. The filtrate wasconcentrated in vacuo and the residue was partitioned between EtOAc (150mL) and water (150 mL). The aqueous layer was acidified to pH 2, andextracted with EtOAc. Silicycle-thiol resin was added to the organiclayer and the suspension was stirred for 10 minutes. The suspension wasfiltered and activated charcoal was added to the filtrate. Thesuspension was stirred at room temperature for another 20 minutes andfiltered. The resulting light yellow solution was concentrated in vacuoand the residue was triturated with CH₂Cl₂ and MeCN. The solid wasfiltered to provide the title compound (280 mg, 13% yield) as a lightyellow solid. The filtrate was concentrated, diluted with EtOAc (20 mL)and filtered to give another batch of desired product (80 mg). MS (ES+)303.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.98 (s, 1H), 7.86 (s, 1H),7.38 (d, J=8.29 Hz, 2H), 7.03 (d, J=8.78 Hz, 2H), 3.82 (s, 3H).

Example 985-(2-Fluoro-4-methoxyphenyl)-6-methyl-1H-indazole-3-carboxylic acid

Step 1 5-Bromo-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole

To a solution of 5-bromo-6-methyl-indazole (500 mg, 2.37 mmol) in THF (6mL) was added dicyclohexylmethylamine (0.63 mL, 3.0 mmol), followed bySEM-chloride (0.50 mL, 2.8 mmol) via syringe. The reaction mixture wasstirred at room temperature for 3 hours. EtOAc (20 mL) was addedfollowed by 0.5 N aqueous NaOH (15 mL). The layers were separated andthe aqueous layer was extracted with EtOAc (3×20 mL). The combinedorganic layers were washed consecutively with water and brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by flash chromatography (0-33% EtOAc/heptane) toprovide the title compound (639 mg, 79% yield). MS (ES+) 343.1 (M+H)⁺.¹H NMR (500 MHz, CDCl₃) δ 8.03 (s, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 5.70(s, 2H), 3.62 (t, J=8.10 Hz, 2H), 2.52 (s, 3H), 0.95 (t, J=8.30 Hz, 2H),0.00 (s, 9H).

Step 25-(2-Fluoro-4-methoxyphenyl)-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole

A mixture of5-bromo-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (600mg, 1.75 mmol), 2-fluoro-4-methoxyphenylboronic acid (320 mg, 1.88 mmol)and 2 N aqueous potassium carbonate solution (1.8 mL, 3.6 mmol) in1,4-dioxane (7.2 mL) was purged with N₂ three times, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (66.0 mg,0.090 mmol) and subjected to microwave irradiation at 90° C. for 40minutes. The reaction mixture was filtered through Celite®, rinsed withEtOAc and concentrated in vacuo. The residue was purified by flashchromatography (0-33% EtOAc/heptane) to provide the title compound (657mg, 92% yield) as a yellow solid. MS (ES⁺) 387.3 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 8.09 (s, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.19 (t, J=8.54Hz, 1H), 6.78 (dd, J=8.42, 2.56 Hz, 1H), 6.73 (dd, J=11.47, 2.44 Hz,1H), 5.75 (s, 2H), 3.87 (s, 3H), 3.64-3.70 (m, 2H), 2.28 (s, 3H),0.93-1.00 (m, 2H), 0.00 (s, 9H).

Step 3 Ethyl5-(2-fluoro-4-methoxyphenyl)-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-3-carboxylate

To a solution of5-(2-fluoro-4-methoxyphenyl)-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole(650 mg, 1.68 mmol) in THF (10 mL) at −78° C. was added n-BuLi (2.5 M inhexanes, 0.74 mL, 1.85 mmol) dropwise via syringe. The reaction wasstirred at −78° C. for 10 minutes, warmed to room temperature for 5minutes, and cooled back to −78° C. A solution of ethyl cyanocarbonate(188 mg, 1.90 mmol) in THF (1 mL) was added via syringe. The coolingbath was removed and the reaction mixture was stirred at roomtemperature for 30 minutes. The reaction was quenched with aqueous NH₄Clsolution and diluted with EtOAc. The organic layer was washed with waterand brine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash chromatography (0-20% EtOAc/heptane) to provide thetitle compound (448 mg, 58% yield). MS (ES+) 459.3 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 7.87 (s, 1H), 7.69 (s, 1H), 7.22 (t, J=8.54 Hz, 1H), 6.81(dd, J=8.42, 2.32 Hz, 1H), 6.75 (dd, J=11.34, 2.32 Hz, 1H), 6.20 (s,2H), 4.49 (q, J=7.07 Hz, 2H), 3.89 (s, 3H), 3.66-3.72 (m, 2H), 2.29 (s,3H), 1.44 (t, J=7.07 Hz, 3H), 0.93-1.00 (m, 2H), 0.00 (s, 9H).

Step 4 Ethyl5-(2-fluoro-4-methoxyphenyl)-6-methyl-1H-indazole-3-carboxylate

To a solution of5-(2-fluoro-4-methoxyphenyl)-6-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-3-carboxylicacid ethyl ester (440 mg, 0.96 mmol) in EtOH (6 mL) was added 3 N HClsolution (1.5 mL, 4.5 mmol). The reaction mixture was heated to 90° C.for 1 hour, cooled to room temperature and concentrated in vacuo. Theresidue was partitioned between water and EtOAc. The organic layer wasdried over Na₂SO₄ and concentrated in vacuo to give the title compound(292 mg, 93% yield) as an amber color solid. MS (ES⁺) 329.3 (M+H)⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.06 (s, 1H), 7.48 (s, 1H), 7.22 (t, J=8.54 Hz,1H), 6.81 (dd, J=8.54, 1.95 Hz, 1H), 6.75 (d, J=11.47 Hz, 1H), 4.52 (q,J=7.16 Hz, 2H), 3.89 (s, 3H), 2.34 (s, 3H), 1.47 (t, J=7.07 Hz, 3H).

Step 5 5-(2-Fluoro-4-methoxyphenyl)-6-methyl-1H-indazole-3-carboxylicacid

To a solution of5-(2-fluoro-4-methoxyphenyl)-6-methyl-1H-indazole-3-carboxylic acidethyl ester (292 mg, 0.89 mmol) in THF (4 mL) was added a solution ofLiOH (298.0 mg, 12.25 mmol) in water (2 mL). The reaction mixture washeated to reflux for 9 hours, and stirred at room temperature for anadditional 48 hours. 1 N HCl solution was added to acidify the solutionto pH 2. White solid formed, which was collected with filtration anddried in a vacuum oven at 50° C. for 4 hours to give the title compound(240 mg, 90% yield) as a solid. MS (ES+) 301.2 (M+H)⁺. ¹H NMR (500 MHz,CD₃OD) δ 7.92 (s, 1H), 7.51 (s, 1H), 7.22 (dd, J=8.70, 8.70 Hz, 1H),6.87 (dd, J=8.42, 2.56 Hz, 1H), 6.81 (dd, J=11.59, 2.56 Hz, 1H), 3.88(s, 3H), 2.30 (s, 3H).

Example 99 6-Chloro-5-(4-ethoxyphenyl)-1H-indazole-3-carboxylic acid

A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg,0.36 mmol), 4-ethoxyphenylboronic acid (63.2 mg, 0.38 mmol), and 2 Naqueous potassium carbonate solution (1.10 mL, 2.18 mmol) in toluene(1.6 mL) and EtOH (2.4 mL) was degassed with N₂ and treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (29.4 mg, 0.036 mmol) under N₂. The reactionmixture was sealed in a pressure tube and heated to 110° C. for 1 hour.The cooled reaction mixture was acidified to pH 5 and concentrated invacuo. The resulting solid was purified by reverse phase HPLC (Column:Waters Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water(v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); 80.0% H₂O/20.0% MeCNlinear to 40.0% H₂O/60.0% MeCN in 10.5 min, 40.0% H₂O/60.0% MeCN linearto 0% H₂O/100% MeCN in 0.5 min HOLD at 0% H₂O/100% MeCN from 11.0 to12.0 min. Flow: 25 mL/min) to give the title compound (5.3 mg, 5%yield). MS (ES+) 317.1 (M+H)⁺. Retention time=2.91 minutes (Column:Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water(v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:Blinear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2mL/min).

Example 100 6-Chloro-5-(4-isopropoxyphenyl)-1H-indazole-3-carboxylicacid

A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg,0.36 mmol), 4-isopropoxyphenylboronic acid (68.6 mg, 0.38 mmol), and 2 Naqueous potassium carbonate solution (1.1 mL, 2.2 mmol) in toluene (1.6mL) and EtOH (2.4 mL) was degassed with N₂ and treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (29.4 mg, 0.036 mmol) under N₂. The reactionmixture was sealed in a pressure tube and heated to 110° C. for 1 hour.The cooled reaction mixture was acidified to pH 5 and concentrated invacuo. The resulting solid was purified by reverse phase HPLC (Column:Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH₄OH in water(v/v); Mobile phase B: 0.03% NH₄OH in MeCN (v/v); 95.0% H₂O/5.0% MeCNlinear to 50.0% H₂O/50.0% MeCN in 10.5 min, 50.0% H₂O/50.0% MeCN linearto 0% H₂O/100% MeCN in 0.5 min HOLD at 0% H₂O/100% MeCN from 11.0 to12.0 min. Flow: 25 mL/min) to give the title compound (13.0 mg, 11%yield). MS (ES+) 331.1 (M+H)⁺. Retention time=3.05 minutes (Column:Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water(v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:Blinear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2mL/min).

Example 1016-Chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-indazole-3-carboxylicacid

Step 1 4′-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)[1,1′-biphenyl]-2-ol

A mixture of 2,2-dimethylpropane-1,3-diol (4.0 g, 38 mmol) and4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-ol (1.0 g,3.4 mmol) in 1,4-dioxane (2 mL) was subjected to microwave irradiationat 210° C. for 1 hour. The cooled reaction mixture was partitionedbetween water (50 mL) and 1:1 EtOAc/heptane (25 mL:25 mL). The organiclayer was washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄and concentrated in vacuo to give the title compound (0.95 g, 99%yield). GC/MS, M=282 at 5.31 min. ¹H NMR (500 MHz, CDCl₃) δ 7.94 (d,J=7.81 Hz, 2H), 7.48 (d, J=7.81 Hz, 2H), 7.31-7.26 (m, 2H), 7.03-6.98(m, 2H), 3.82 (s, 4H), 1.08-1.04 (m, 6H).

Step 26-Chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-indazole-3-carboxylicacid

A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (900 mg,3.27 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (360 mg,0.49 mmol) was purged with N₂. To this mixture was added4′-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1′-biphenyl]-2-ol (922 mg,3.27 mmol) in toluene (5.0 mL) and EtOH (15.0 mL), followed by 2 Naqueous potassium carbonate solution (6.0 mL, 12 mmol). The reactionmixture was heated to 100° C. for 48 hours, cooled to room temperatureand poured into 1 N aqueous citric acid (15 mL). The aqueous layer wasextracted with EtOAc (3×25 mL). The combined organic layers were driedover Na₂SO₄ and concentrated in vacuo. The crude material was purifiedby reverse phase chromatography (C-18 column, 10-40% MeCN/water) to givethe title compound (258 mg, 22% yield) as a solid. MS (ES⁺) 365.0(M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.18 (s, 1H), 7.82 (s, 1H), 7.68 (d,2H), 7.50 (d, 2H), 7.36 (d, 1H), 7.19 (dt, 1H), 6.97-6.92 (m, 2H).

Example 1026-Chloro-5-(4-(2-hydroxypropan-2-yl)phenyl)-1H-indazole-3-carboxylicacid

To a mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg,0.36 mmol) and2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propan-2-ol(114 mg, 0.44 mmol) in toluene (1.5 mL) and EtOH (1.5 mL) was added 2 Naqueous potassium carbonate solution (0.7 mL, 1.4 mmol). The reactionmixture was degassed with N₂ for 10 minutes, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg,0.018 mmol), and heated to reflux for 16 hours. After cooling to roomtemperature, the reaction was quenched with 1 N NaOH (1 mL). The mixturewas stirred for 30 minutes, acidified with 1 N HCl to pH 5 and extractedwith EtOAc. The organic layer was washed with brine, dried over Na₂SO₄and concentrated in vacuo. The crude material was purified by reversephase chromatography (Biotage C18 column, 0-40% MeCN/water) to give thetitle compound (42 mg, 35% yield) as a solid. MS (ES−) 329.1 (M−H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.06 (s, 1H), 7.74 (s, 1H), 7.55 (d, J=8.20 Hz,2H), 7.37 (d, J=8.20 Hz, 2H), 1.57 (s, 6H).

Example 1036-Chloro-5-(4-(1-hydroxycyclobutyl)phenyl)-1H-indazole-3-carboxylic acid

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (800 mg,2.34 mmol), 1-(4-bromophenyl)cyclobutanol (500 mg, 2.20 mmol), potassiumacetate (1.0 g, 10 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (136 mg, 0.17 mmol) in 1,4-dioxane (12 mL) wasdegassed with N₂ for 5 minutes, and subjected to microwave irradiationat 115° C. for 1 hour. The cooled reaction mixture was filtered througha cotton plug and concentrated in vacuo. The resulting dark solid wasdissolved in 1:1 toluene/EtOH (10 mL) and to this solution was added5-bromo-6-chloro-1H-indazole-3-carboxylic acid (551 mg, 2.00 mmol)followed by 2 N aqueous potassium carbonate solution (4.0 mL, 8.0 mmol).The reaction mixture was degassed with N₂, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (98.0 mg, 0.12 mmol) under N₂, and heated in asealed pressure tube to 110° C. for 3 hours. The cooled reaction mixturewas concentrated in vacuo and the residue was partitioned between EtOAc(20 mL) and 2 N citric acid solution (20 mL). The layers were separatedand the aqueous layer was extracted with EtOAc. The combined organiclayers were dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by reverse phase chromatography (Biotage C18column, 20-60% MeCN/water) to give the title compound (78 mg, 10% yield)as a solid. MS (ES−) 341.5 (M−H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.01 (s,1H), 7.88 (s, 1H), 7.59 (d, J=8.05 Hz, 2H), 7.42 (d, J=8.05 Hz, 2H),5.55 (br. s, 1H), 2.39-2.46 (m, 2H), 2.23-2.35 (m, 2H), 1.89-2.01 (m,1H), 1.64-1.76 (m, 1H).

Example 1046-Chloro-5-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-indazole-3-carboxylicacid

A mixture of 4-(4-bromophenyl)tetrahydrofuran (300 mg, 1.24 mmol),5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (309 mg, 1.37 mmol),potassium acetate (582 mg, 5.93 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (45.4 mg,0.062 mmol) in 1,4-dioxane (10 mL) was sealed in a pressure tube andstirred at 110° C. for 12 hours. The resulting suspension was cooled,filtered through Celite®, rinsed with EtOAc and concentrated in vacuo.To the residue was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid(410 mg, 1.49 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (51 mg,0.062 mmol), 2 N aqueous potassium carbonate solution (2.5 mL, 5.0mmol), EtOH (5 mL) and toluene (5 mL). The reaction mixture was sealedin a pressure tube, degassed with N₂ for 10 minutes and stirred at 110°C. for 16 hours. After cooling to room temperature, the reaction wasquenched with 1 N NaOH (1 mL). The mixture was stirred for 30 minutes,acidified with 1 N HCl to pH 5 and extracted with EtOAc three times. Thecombined organic layers were concentrated in vacuo and the crudematerial was purified by reverse phase chromatography (Biotage C18column, 0-40% MeCN/water) to give a solid (62.0 mg). The solid wassuspended in MeCN (2 mL) and water (0.2 mL), heated to 100° C. andslowly cooled to room temperature over 12 hours. The resultingprecipitate was filtered and washed with MeCN to provide the titlecompound (37 mg, 8% yield) as a crystalline solid. MS (ES+) 357.0(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (s, 1H), 7.87 (s, 1H), 7.40 (d,J=8.29 Hz, 2H), 7.36 (d, J=8.29 Hz, 2H), 3.98 (dd, J=10.98, 2.93 Hz,2H), 3.47 (td, J=11.22, 2.68 Hz, 2H), 2.85 (ddd, J=16.34, 11.47, 5.12Hz, 1H), 1.67-1.80 (m, 4H).

Example 105 5-(4-Acetylphenyl)-6-chloro-1H-indazole-3-carboxylic acid

To a mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (200 mg,0.73 mmol) and 4-acetylphenylboronic acid (131 mg, 0.80 mmol) in toluene(2 mL) and EtOH (1 mL) was added 2 N aqueous potassium carbonatesolution (1.45 mL, 2.90 mmol). The resulting mixture was degassed withN₂ for 10 minutes, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg,0.036 mmol), and heated to reflux for 16 hours. The cooled reaction wasquenched with saturated NH₄Cl and the mixture was filtered. The filtratewas acidified with 1 N HCl to pH 5 and extracted with EtOAc. The organiclayer was dried over Na₂SO₄ and concentrated in vacuo. The resultingcrude material was purified by reverse phase chromatography (Biotage C18column, 0-40% MeCN/water) to give the title compound (82 mg, 40% yield)as a solid. MS (ES+) 315.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (s,1H), 8.01 (d, J=8.39 Hz, 2H), 7.82 (s, 1H), 7.57 (d, J=8.20 Hz, 2H),2.60 (s, 3H).

Example 1066-Chloro-5-(4-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-3-carboxylicacid

To 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (75.0 mg, 0.27 mmol)in a 5 mL microwave vial was sequentially added1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]piperazine(82.2 mg, 0.27 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.0 mg,0.027 mmol), 1,4-dioxane (2 mL) and 2 N aqueous potassium carbonatesolution (0.4 mL, 0.81 mmol). The reaction mixture was degassed withargon and subjected to microwave irradiation at 110° C. for 50 minutes.The cooled reaction mixture was acidified to pH 5 with 1 N HCl anddiluted with EtOAc (10 mL). The organic layer was washed with brine (6mL), dried over MgSO₄, and concentrated in vacuo. The resulting solidwas purified by reversed phase HPLC (Column: Waters Sunfire C18 19×100,5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05%TFA in MeCN (v/v); Gradient: HOLD at 90.0% H₂O/10.0% MeCN for 1.0 min.90.0% H₂O/10.0% MeCN linear to 60.0% H₂O/40.0% MeCN in 6.75 min, linearto 0% H₂O/100% MeCN to 7.0 min. HOLD at 0% H₂O/100% MeCN from 7.0 to 8.0min. Flow: 30 mL/min.) to afford the title compound (4.3 mg, 4% yield).MS (ES+) 371.0 (M+H)⁺. Retention time=1.83 minutes (Column: WatersAtlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v);Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 1075-(4-(4-Acetylpiperazin-1-yl)phenyl)-6-chloro-1H-indazole-3-carboxylicacid

To 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (75.0 mg, 0.27 mmol)in a 5 mL microwave vial was sequentially added1-{4-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]piperazin-1-yl}ethanone(89.8 mg, 0.27 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.0 mg,0.027 mmol), 1,4-dioxane (2 mL) and 2 N aqueous potassium carbonatesolution (0.4 mL, 0.81 mmol). The reaction mixture was degassed withargon and subjected to microwave irradiation at 110° C. for 50 minutes.The cooled reaction mixture was acidified to pH 5 with 1 N HCl anddiluted with EtOAc (10 mL). The organic layer was washed with brine (6mL), dried over MgSO₄ and concentrated in vacuo. The resulting solid waspurified by reversed phase HPLC (Column: Waters Sunfire C18 19×100, 5μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFAin MeCN (v/v); Gradient: HOLD at 80.0% H₂O/20.0% MeCN for 1.0 min. 80.0%H₂O/20.0% MeCN linear to 60.0% H₂O/40.0% MeCN in 6.75 min, linear to 0%H₂O/100% MeCN to 7.0 min. HOLD at 0% H₂O/100% MeCN from 7.0 to 8.0 min.Flow: 30 mL/min.) to afford the title compound (7.6 mg, 7% yield). MS(ES+) 399.1 (M+H)⁺. Retention time=2.25 minutes (Column: Waters AtlantisdC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobilephase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:Bin 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 ml/min).

Example 1086-Chloro-5-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-1H-indazole-3-carboxylicacid

Step 12-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-1,1,1-trifluoropropan-2-ol

A mixture of 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (300 mg, 1.12mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (420 mg, 1.23mmol), potassium acetate (500 mg, 5.10 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (90 mg, 0.11mmol) was purged with N₂, suspended in degassed 1,4-dioxane (2.0 mL) andsubjected to microwave irradiation at 110° C. for 60 minutes. The cooledreaction mixture was diluted with water (15 mL) and extracted with EtOAc(2×20 mL). The combined organic layers were washed with water and brine,dried over MgSO₄ and concentrated in vacuo. The resulting black oil waspurified by flash chromatography (0-67% EtOAc/heptane) to afford thetitle compound (249 mg, 74% yield) as a pale yellow oil. GC/MS, M=302 at3.58 min. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J=8.39 Hz, 2H), 7.54 (d,J=8.00 Hz, 2H), 3.76 (s, 4H), 1.77 (s, 3H), 1.01 (s, 6H).

Step 26-Chloro-5-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-1H-indazole-3-carboxylicacid

A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (30.0 mg,0.11 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.3 mg,0.010 mmol) was purged with N₂. To this mixture was added2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-phenyl]-1,1,1-trifluoropropan-2-ol(35.0 mg, 0.12 mmol) in toluene (1.0 mL) and EtOH (0.5 mL), followed by2 N aqueous potassium carbonate solution (0.22 mL, 0.44 mmol). Thereaction mixture was heated to 110° C. for 18 hours, cooled to roomtemperature and concentrated in vacuo. The resulting solid waspartitioned between water and EtOAc, and acidified to pH 5 with aqueous1 N citric acid. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo. The crude material was purified by reverse phaseHPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05%TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); HOLD at100.0% H₂O/0.0% MeCN for 1.0 min. 100.0% H₂O/0.0% MeCN linear to 5.0%H₂O/95.0% MeCN in 6.75 min, linear to 0% H₂O/100% MeCN to 7.0 min. HOLDat 0% H₂O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min) to give thetitle compound (6.5 mg, 15% yield).

MS (ES⁺) 384.9 (M+H)⁺. Retention time=2.62 minutes (Column: WatersAtlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v);Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 1096-Chloro-5-(4-(2-hydroxyethyl)phenyl)-1H-indazole-3-carboxylic acid

To a solution of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (75 mg,0.27 mmol),2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (75 mg,0.30 mmol) in EtOH (0.5 mL) and toluene (0.5 mL) was added 2 N aqueouspotassium carbonate solution (0.5 mL, 1.0 mmol). The reaction mixturewas degassed with N₂ for 5 minutes, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.4 mg,0.014 mmol) and degassed with N₂ for another 5 minutes. The suspensionwas sealed in a pressure tube and heated to 130° C. for 1 hour. As thereaction progressed, the suspension became clear, turned to orange andthen dark brown. The reaction mixture was diluted with EtOAc (5 mL) andwater (5 mL), and filtered through a syringe filter. The aqueous layerwas acidified to pH 5 by 1 N HCl solution, and extracted with EtOAc. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by reverse phase HPLC (Column: Waters Sunfire C1819×100 mm, 5 μm; Mobile phase A: 0.05% Formic acid in water (v/v);Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 80.0% H₂O/20.0%MeCN for 1.0 min. 80.0% H₂O/20.0% MeCN linear to 60.0% H₂O/40.0% MeCN in6.75 min, linear to 0% H₂O/100% MeCN to 7.0 min. HOLD at 0% H₂O/100%MeCN from 7.0 to 8.0 min. Flow: 30 mL/min) to provide the title compound(11.5 mg, 13% yield). MS (ES+) 317.1 (M+H)⁺. Retention time=2.27 minutes(Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFAin water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2mL/min).

Example 110 6-Chloro-5-(4-cyclohexylphenyl)-1H-indazole-3-carboxylicacid

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (75.0 mg,0.22 mmol), oven dried potassium acetate (94.1 mg, 0.95 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19.0 mg,0.023 mmol), and 1-bromo-4-cyclohexylbenzene (49.5 mg, 0.21 mmol) in1,4-dioxane (2 mL) was degassed with N₂ for 10 minutes, and subjected tomicrowave irradiation at 115° C. for one hour. The black reactionmixture was cooled, filtered through cotton, and concentrated in vacuoto give a dark solid. To the dark solid was added5-bromo-6-chloro-1H-indazole-3-carboxylic acid (55.6 mg, 0.20 mmol), 2 Naqueous potassium carbonate solution (0.40 mL, 0.81 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (16.3 mg, 0.020 mmol). The reaction mixture wasdiluted with degassed toluene (1 mL) and EtOH (1 mL), and heated at 110°C. for 18 hours in a sealed reaction vessel. The cooled reaction mixturewas concentrated in vacuo and partitioned between 2 N citric acid (15mL) and EtOAc (15 mL). The layers were separated, and the aqueous phasewas extracted with EtOAc (15 mL). The combined organic layers were driedover Na₂SO₄ and concentrated in vacuo to give a dark oil, which waspurified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5μm; Mobile phase A: 0.03% NH₄OH in water (v/v); Mobile phase B: 0.03%NH₄OH in MeCN (v/v); 80.0% H₂O/20.0% MeCN linear to 40% H₂O/60% MeCN in8.5 min, 40% H₂O/60% MeCN linear to 0% H₂O/100% MeCN in 0.5 min, HOLD at0% H₂O/100% MeCN to 10.0 min. Flow: 25 mL/min) to give the titlecompound (6.2 mg, 9% yield). MS (ES+) 355.1 (M+H)⁺. Retention time=3.65minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A:0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v);Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to5.0 min. Flow: 2 mL/min).

Example 1116-Chloro-5-(4-(hydroxymethyl)phenyl)-1H-indazole-3-carboxylic acid

A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (200.0 mg,0.73 mmol), 4-(hydroxymethyl)phenylboronic acid (90.0 mg, 0.59 mmol), 2N aqueous potassium carbonate (1.1 mL, 2.2 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I I) (60.0 mg,0.073 mmol) in toluene (1.5 mL) and EtOH (2.3 mL) was degassed with N₂for 3 minutes and heated to 110° C. for 5 hours. The reaction mixturewas cooled to room temperature and concentrated in vacuo. The residuewas acidified to pH 5 and concentrated in vacuo. The crude material waspurified by reverse phase HPLC (Column: Phenomenex Synergi C18 150×30mm, 4 μm; 28% MeCN in water (0.225% TFA) to 28% MeCN in water (0.225%TFA) for 12 min; Flow Rate: 30 mL/min) to afford the title compound (27mg, 11% yield) as a white solid. MS (ES+) 302.9 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.11 (s, 1H), 7.76 (s, 1H), 7.45 (m, 4H), 4.69 (s, 2H).

Example 112 6-Chloro-5-(3-hydroxyphenyl)-1H-indazole-3-carboxylic acid

A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg,0.36 mmol), 3-hydroxyphenylboronic acid (51.0 mg, 0.36 mmol), potassiumcarbonate (301 mg, 2.18 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30.0 mg,0.036 mmol) in toluene (1.5 mL) and water (1.1 mL) was degassed with N₂for 3 minutes and heated to 110° C. for 16 hours. The reaction mixturewas cooled to room temperature and concentrated in vacuo. The brownresidue was acidified to pH 4 with 1 N HCl and extracted with n-butanol(3×20 mL). The combined organic layers were washed with brine (2×20 mL),dried over Na₂SO₄ and concentrated in vacuo. The crude material waspurified by reverse phase HPLC (Column: Phenomenex Synergi C18 150×30mm, 4 μm; 25% MeCN in water (0.225% TFA) to 45% MeCN in water (0.225%TFA) to afford the title compound (4 mg, 4% yield) as a white solid.

MS (ES+) 289.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H), 8.04(s, 1H), 7.83 (s, 1H), 7.28 (t, J=8.20 Hz, 1H), 6.82 (m, 3H).

Example 1136-Chloro-5-(2,3-dihydrobenzofuran-5-yl)-1H-indazole-3-carboxylic acid

To a solution of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (100 mg,0.36 mmol), 2,3-dihydrobenzofuran-5-boronic acid (65.0 mg, 0.39 mmol) inEtOH (0.5 mL) and toluene (0.5 mL) was added 2 N aqueous potassiumcarbonate solution (0.5 mL, 1.0 mmol). The reaction mixture was degassedwith N₂ for 5 minutes, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg,0.018 mmol) and degassed with N₂ for another 5 minutes. The suspensionwas sealed in a pressure tube and heated to 130° C. for 1 hour. As thereaction progressed, the suspension became clear, turned to orange andthen dark brown. The reaction mixture was diluted with EtOAc (5 mL) andwater (5 mL), and filtered through a syringe filter. The aqueous layerwas acidified to pH 5 by 1 N HCl solution, and extracted with EtOAc. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by reverse phase HPLC (Column: Waters XBridge C1819×100 mm, 5 μm; Mobile phase A: 0.03% NH₄OH in water (v/v); Mobilephase B: 0.03% NH₄OH in MeCN (v/v); 95.0% H₂O/5.0% MeCN linear to 50.0%H₂O/50.0% MeCN in 8.5 min, 50.0% H₂O/50.0% MeCN linear to 0% H₂O/100%MeCN in 0.5 min HOLD at 0% H₂O/100% MeCN from 9.0 to 10.0 min. Flow: 25mL/min) to provide the title compound (24.8 mg, 22% yield). MS (ES+)315.1 (M+H)⁺. Retention time=2.68 minutes (Column: Waters Atlantis dC184.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phaseB: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 1146-Chloro-5-(4-(1-methylpiperidin-4-yl)phenyl)-1H-indazole-3-carboxylicacid

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (92.0 mg,0.27 mmol), oven dried potassium acetate (116 mg, 1.18 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (22 mg, 0.027 mmol) and4-(4-bromophenyl)-1-methylpiperidine (65 mg, 0.26 mmol) in 1,4-dioxane(2.6 mL) was degassed with N₂ for 10 minutes, sealed in a pressure tube,and heated to 100° C. for 2 hours. The cooled reaction mixture wasfiltered through cotton and concentrated in vacuo to give a dark solid.To the dark solid was added 5-bromo-6-chloro-1H-indazole-3-carboxylicacid (59.8 mg, 0.22 mmol), 2 N aqueous potassium carbonate solution (0.4mL, 0.87 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (18 mg, 0.022 mmol). The reaction mixture wasdiluted with degassed toluene (0.8 mL) and EtOH (0.8 mL), sealed in apressure tube and heated at 100° C. for 1.5 hours then 75° C. for anadditional 16 hours. The cooled reaction mixture was concentrated invacuo. The resulting dark solid was purified by reverse phase HPLC(Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH₄OHin water (v/v); Mobile phase B: 0.03% NH₄OH in MeCN (v/v); 95.0%H₂O/5.0% MeCN linear to 0% H₂O/100% MeCN in 8.5 min, HOLD at 0% H₂O/100%MeCN to 10.0 min. Flow: 25 mL/min) to give the title compound (8.2 mg,9% yield). MS (ES+) 370.2 (M+H)⁺. Retention time=2.00 minutes (Column:Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water(v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:Blinear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2mL/min).

Example 1156-Chloro-5-(4-(1-hydroxy-2-methylpropan-2-yl)phenyl)-1H-indazole-3-carboxylicacid

A suspension of 2-(4-bromophenyl)-2-methylpropan-1-ol (168 mg, 0.73mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (275 mg, 0.81mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30mg, 0.037 mmol) and potassium acetate (216 mg, 2.20 mmol) in 1,4-dioxane(2 mL) was sealed in a pressure tube and heated to 130° C. for 1 hour.To the mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid(100 mg, 0.36 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg,0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol)and EtOH (2 mL). The reaction mixture was sealed and heated to 130° C.for 1 hour. Water (3 mL) was added to the reaction mixture, followed by1 N HCl solution to adjust the pH to 2. The layers were separated andthe aqueous layer was extracted with EtOAc (3×5 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Thecrude material was purified by reverse phase HPLC (Column: WatersXBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH₄OH in water (v/v);Mobile phase B: 0.03% NH₄OH in MeCN (v/v); 90.0% H₂O/10.0% MeCN linearto 70.0% H₂O/30.0% MeCN in 8.5 min, 70.0% H₂O/30.0% MeCN linear to 0%H₂O/100% MeCN in 0.5 min HOLD at 0% H₂O/100% MeCN from 9.0 to 10.0 min.Flow: 25 mL/min) to afford the title compound (25.1 mg, 20% yield). MS(ES+) 345.1 (M+H)⁺. Retention time=1.59 minutes (Column: Waters XBridgedC18 4.6×50 mm, 5 μm; Mobile phase A: 0.03% NH₄OH in water (v/v); Mobilephase B: 0.03% NH₄OH in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 ml/min).

Example 1166-Chloro-5-(2,3-dihydro-1H-inden-5-yl)-1H-indazole-3-carboxylic acid

A suspension of 5-bromoindane (100.0 mg, 0.51 mmol),5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (191 mg, 0.56 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42.0 mg,0.025 mmol) and potassium acetate (150 mg, 1.50 mmol) in 1,4-dioxane (1mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. Tothis mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid(100 mg, 0.36 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg,0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol)and EtOH (2 mL). The reaction mixture was sealed and heated to 130° C.for 1 hour. Water (3 mL) was added to the reaction mixture, followed by1 N HCl solution to adjust the pH to 2. The layers were separated andthe aqueous layer was extracted with EtOAc (3×5 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated in vacuo. Thecrude material was purified by reverse phase HPLC (Column: WatersXBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH₄OH in water (v/v);Mobile phase B: 0.03% NH₄OH in MeCN (v/v); 80.0% H₂O/20.0% MeCN linearto 70.0% H₂O/30.0% MeCN in 8.5 min, 70.0% H₂O/30.0% MeCN linear to 0%H₂O/100% MeCN in 0.5 min HOLD at 0% H₂O/100% MeCN from 9.0 to 10.0 min.Flow: 25 mL/min) to afford the title compound (6.2 mg, 6% yield). MS(ES+) 313.1 (M+H)⁺. Retention time=3.11 minutes (Column: Waters AtlantisdC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobilephase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:Bin 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 1175-(4-(1-Acetylpiperidin-4-yl)phenyl)-6-chloro-1H-indazole-3-carboxylicacid

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (110 mg,0.32 mmol), oven dried potassium acetate (139 mg, 1.41 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (26 mg, 0.032 mmol), and1-(4-(4-bromophenyl)piperidin-1-yl)ethanone (86 mg, 0.30 mmol) in1,4-dioxane (3.1 mL) was degassed with N₂ for 10 minutes, and subjectedto microwave irradiation at 115° C. for 1 hour. The cooled reactionmixture was filtered through cotton and concentrated in vacuo to give adark solid. To the dark solid was added5-bromo-6-chloro-1H-indazole-3-carboxylic acid (68.9 mg, 0.25 mmol), 2 Naqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (20.4 mg, 0.025 mmol). The reaction mixture wasdiluted with degassed toluene (0.8 mL) and EtOH (0.8 mL), sealed in apressure tube and heated at 100° C. for 1 hour then 75° C. for anadditional 16 hours. The cooled reaction mixture was concentrate invacuo, and the residue was partitioned between 0.5 N HCl (14 mL) andEtOAc (15 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (3×8 mL). The combined organic layers were driedover Na₂SO₄ and concentrated in vacuo. The resulting reddish solid waspurified by reverse phase HPLC Column: Waters XBridge C18 19×100 mm, 5μm; Mobile phase A: 0.03% NH₄OH in water (v/v); Mobile phase B: 0.03%NH₄OH in MeCN (v/v); 85.0% H₂O/15.0% MeCN linear to 65.0% H₂O/35.0% MeCNin 10.5 min, 65.0% H₂O/35.0% MeCN linear to 0% H₂O/100% MeCN in 0.5 minHOLD at 0% H₂O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to givethe title compound (14.4 mg, 15% yield). MS (ES+) 398.2 (M+H)⁺.Retention time=2.55 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFAin MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 1186-Chloro-5-(4-methoxyphenyl)-N-(phenylsulfonyl)-1H-indazole-3-carboxamide

Step 1 6-Chloro-5-(4-methoxyphenyl)-1H-indazole-3-carboxylic acidp-tolyl ester

A mixture of 6-chloro-5-(4-methoxyphenyl)-1H-indazole-3-carboxylic acid(547 mg, 1.81 mmol) in thionyl chloride (10 mL) was heated to 60° C. for4 hours, cooled to room temperature and concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ (20 mL) and treated with p-cresol (399mg, 3.61 mmol) followed by triethylamine (369 mg, 3.61 mmol). Thereaction mixture was stirred for 16 hours and quenched with water (20mL). The layers were separated and the organic phase was concentrated invacuo. The residue was purified by flash chromatography (25-50%EtOAc/heptane) to give the title compound (192 mg, 27% yield).

MS (ES⁺) 393.2 (M+1)⁺.

Step 26-Chloro-5-(4-methoxyphenyl)-N-(phenylsulfonyl)-1H-indazole-3-carboxamide

A mixture of benzenesulfonamide (25.6 mg, 0.163 mmol) and potassiumtert-butoxide (22.0 mg, 0.196 mmol) in THF (10 mL) was stirred for 10minutes, and treated with6-chloro-5-(4-methoxyphenyl)-1H-indazole-3-carboxylic acid p-tolyl ester(64 mg, 0.16 mmol). The reaction mixture was heated to 65° C. for 16hours, cooled to room temperature and concentrated in vacuo. The residuewas partitioned between water (5 mL) and EtOAc (5 mL), and the layerswere separated. The organic layer was concentrated in vacuo and thecrude material was purified by reverse phase HPLC (Column: WatersSunfire C18 19×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v);Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 60:40 A:B linear to30:70 A:B in 8.5 min to 100% B to 9.0 min, hold at 100% B from 9.0 to10.0 min. Flow: 25 mL/min) to give the title compound (2.2 mg, 3%yield). MS (ES⁺) 442.0 (M+1)⁺. Retention time=3.29 minutes (Column:Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water(v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:Blinear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2mL/min).

Example 1196-Chloro-5-(4-(2-hydroxyethoxy)phenyl)-1H-indazole-3-carboxylic acid

A suspension of 2-(4-bromophenoxy)ethanol (100 mg, 0.46 mmol),5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (173 mg, 0.50 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (38.0 mg,0.025 mmol) and potassium acetate (135 mg, 1.38 mmol) in 1,4-dioxane (1mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. Tothe mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid(100 mg, 0.36 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg,0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol)and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1hour. Water (3 mL) was added to the reaction mixture, followed by 1 NHCl solution to adjust the pH to 2. The layers were separated and theaqueous layer was extracted with EtOAc (3×5 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by reverse phase HPLC (Column: Waters Sunfire C1819×100 mm, 5 μm; Mobile phase A: 0.05% Formic acid in water (v/v);Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 75.0% H₂O/25.0%MeCN for 1.0 min. 75.0% H₂O/25.0% MeCN linear to 45.0% H₂O/55.0% MeCN in6.75 min, linear to 0% H₂O/100% MeCN to 7.0 min. HOLD at 0% H₂O/100%MeCN from 7.0 to 8.0 min. Flow: 30 ml/min) to afford the title compound(23.1 mg, 15% yield). MS (ES+) 333.0 (M+H)⁺. Retention time=2.19 minutes(Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFAin water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2mL/min).

Example 1206-Chloro-5-(4-((1S,3S)-3-hydroxycyclobutyl)phenyl)-1H-indazole-3-carboxylicacid

A suspension of 3-(4-bromophenyl)cyclobutanol (90.6 mg, 0.37 mmol),5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (136 mg, 0.37 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg,0.018 mmol) and potassium acetate (107 mg, 1.09 mmol) in 1,4-dioxane (1mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. Tothe mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid(100 mg, 0.36 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg,0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol)and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1hour. Water (3 mL) was added to the reaction mixture, followed by 1 NHCl solution to adjust the pH to 2. The layers were separated and theaqueous layer was extracted with EtOAc (3×5 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by reverse phase HPLC (Column: Waters Sunfire C1819×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phaseB: 0.05% TFA in MeCN (v/v); 95.0% H₂O/5.0% MeCN linear to 0% H₂O/100%MeCN in 10.5 min, HOLD at 0% H₂O/100% MeCN to 12.0 min. Flow: 25 mL/min)to afford the title compound (17.4 mg, 14% yield). MS (ES+) 343.1(M+H)⁺. Retention time=2.45 minutes (Column: Waters Atlantis dC18 4.6×50mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B:0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 1216-Chloro-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indazole-3-carboxylicacid

A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (40.0 mg,0.14 mmol), (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (27.4 mg,0.152 mmol) and 2 N aqueous potassium carbonate solution (0.2 mL, 0.4mmol) in toluene (0.3 mL) and EtOH (0.7 mL) was purged with N₂, andtreated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)under N₂. The reaction mixture was heated to 100° C. for 48 hours,cooled to room temperature and concentrated in vacuo. The crude materialwas purified by reverse phase HPLC (Column: Waters XBridge C18 19×100mm, 5 μm; Mobile phase A: 0.03% NH₄OH in water (v/v); Mobile phase B:0.03% NH₄OH in MeCN (v/v); 95.0% H₂O/5.0% MeCN linear to 50.0% H₂O/50.0%MeCN in 10.5 min, 50.0% H₂O/50.0% MeCN linear to 0% H₂O/100% MeCN in 0.5min HOLD at 0% H₂O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) toafford the title compound (4.7 mg, 10% yield). MS (ES+) 331.1 (M+H)⁺.Retention time=2.62 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFAin MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 1225-(4-(1-Carbamoylcyclobutyl)phenyl)-6-chloro-1H-indazole-3-carboxylicacid

A suspension of 1-(4-bromophenyl)cyclobutanecarboxylic acid amide (101mg, 0.37 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (136mg, 0.37 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg,0.018 mmol) and potassium acetate (107 mg, 1.09 mmol) in 1,4-dioxane (1mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. Tothe mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid(100 mg, 0.36 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg,0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol)and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1hour. Water (3 mL) was added to the reaction mixture, followed by 1 NHCl solution to adjust the pH to 2. The layers were separated and theaqueous layer was extracted with EtOAc (3×5 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by reverse phase HPLC (Column: Waters Sunfire C1819×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phaseB: 0.05% TFA in MeCN (v/v); 95.0% H₂O/5.0% MeCN linear to 0% H₂O/100%MeCN in 10.5 min, HOLD at 0% H₂O/100% MeCN to 12.0 min. Flow: 25 mL/min)to afford the title compound (4.3 mg, 3% yield). MS (ES+) 343.1 (M+H)⁺.Retention time=2.45 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFAin MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 1235-(4-(2-Amino-2-oxoethyl)phenyl)-6-chloro-1H-indazole-3-carboxylic acid

A suspension of 2-(4-bromophenyl)acetamide (85.0 mg, 0.37 mmol),5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (136 mg, 0.37 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg,0.018 mmol) and potassium acetate (107 mg, 1.09 mmol) in 1,4-dioxane (1mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. Tothe mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid(100 mg, 0.36 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg,0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1 mmol)and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1hour. Water (3 mL) was added to the reaction mixture, followed by 1 NHCl solution to adjust the pH to 2. The layers were separated and theaqueous layer was extracted with EtOAc (3×5 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by reverse phase HPLC (Column: Waters Sunfire C1819×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phaseB: 0.05% TFA in MeCN (v/v); 95.0% H₂O/5.0% MeCN linear to 0% H₂O/100%MeCN in 10.5 min, HOLD at 0% H₂O/100% MeCN to 12.0 min. Flow: 25 mL/min)to afford the title compound (3.3 mg, 3% yield). MS (ES+) 330.1 (M+H)⁺.Retention time=2.04 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFAin MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 124(±)-6-Chloro-5-(4-(tetrahydrofuran-3-yl)phenyl)-1H-indazole-3-carboxylicacid

Step 1 (±)-3-(4-Bromophenyl)tetrahydrofuran

A mixture of 4-bromophenylboronic acid (1.7 g, 8.1 mmol), nickel iodide(102 mg, 0.32 mmol), solid sodium hexamethyldisilazide (1.6 g, 8.1 mmol)and trans-2-aminocyclohexanol (49.0 mg, 0.32 mmol) was sealed in amicrowave vial, diluted with dry i-PrOH (7 mL), and evacuated/backfilledwith N₂ three times. The reaction mixture was stirred at roomtemperature for 5 minutes, treated with a solution of3-iodotetrahydrofuran (800 mg, 4.04 mmol) in i-PrOH (1 mL) andevacuated/backfilled with N₂. The reaction mixture was subjected tomicrowave irradiation at 80° C. for 20 minutes. The cooled reactionmixture was poured into 0.3 N HCl (30 mL) and extracted withheptane/EtOAc (2:1, 3×20 mL). The combined organic layers were driedover Na₂SO₄ and concentrated in vacuo to give a yellow solid. The crudematerial was purified by flash chromatography (0-5% EtOAc/Heptane) togive the title compound (471 mg, 51% yield) as a clear oil. ¹H NMR (400MHz, CDCl₃) δ 7.41 (d, J=8.39 Hz, 2H), 7.11 (d, J=8.39 Hz, 2H), 4.09 (t,J=8.00 Hz, 1H), 4.04 (td, J=8.39, 4.69 Hz, 1H), 3.89 (q, J=8.00 Hz, 1H),3.65-3.70 (m, 1H), 3.34 (quin, J=7.66 Hz, 1H), 2.35 (dtd, J=12.37, 7.77,7.77, 4.68 Hz, 1H), 1.94 (dq, J=12.37, 8.04 Hz, 1H).

Step 2(±)-6-Chloro-5-(4-(tetrahydrofuran-3-yl)phenyl)-1H-indazole-3-carboxylicacid

A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (110 mg,0.32 mmol), oven dried potassium acetate (140 mg, 1.42 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (27.0 mg, 0.033 mmol), and(±)-3-(4-bromophenyl)tetrahydrofuran (70.0 mg, 0.31 mmol) in 1,4-dioxane(3.1 mL) was degassed with N₂ for 10 minutes, and subjected to microwaveirradiation at 115° C. for 1 hour. The cooled reaction mixture wasfiltered through cotton and concentrated in vacuo to give a dark solid.To the dark solid was added 5-bromo-6-chloro-1H-indazole-3-carboxylicacid (75.0 mg, 0.270 mmol), 2 N aqueous potassium carbonate solution(0.543 mL, 1.09 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (22.0 mg, 0.027 mmol). The reaction mixture wasdiluted with degassed toluene (0.8 mL) and EtOH (0.8 mL), and heated at100° C. for 1.5 hours in a sealed tube. The cooled reaction mixture wasconcentrated in vacuo, and the residue was partitioned between 0.5 N HCl(15 mL) and EtOAc (10 mL). The layers were separated and the aqueouslayer was extracted with EtOAc (3×10 mL). The combined organic layerswere dried over Na₂SO₄ and concentrated in vacuo. The resulting brownsolid was purified by reverse phase HPLC (Column: Waters XBridge C1819×100 mm, 5 μm; Mobile phase A: 0.03% NH₄OH in water (v/v); Mobilephase B: 0.03% NH₄OH in MeCN (v/v); 95.0% H₂O/5.0% MeCN linear to 50.0%H₂O/50.0% MeCN in 10.5 min, 50.0% H₂O/50.0% MeCN linear to 0% H₂O/100%MeCN in 0.5 min HOLD at 0% H₂O/100% MeCN from 11.0 to 12.0 min. Flow: 25mL/min) to give the title compound (9.6 mg, 10% yield). MS (ES+) 343.1(M+H)⁺. Retention time=2.63 minutes (Column: Waters Atlantis dC18 4.6×50mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B:0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 1256-Chloro-5-(4-(1-methoxyethyl)phenyl)-1H-indazole-3-carboxylic acid

A mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (40.0 mg,0.14 mmol), 4-(1-methoxyethyl)phenylboronic acid (27.4 mg, 0.152 mmol)and 2 N aqueous potassium carbonate solution (0.2 mL, 0.4 mmol) intoluene (0.3 mL) and EtOH (0.7 mL) was purged with N₂, and treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) under N₂.The reaction mixture was heated to 100° C. for 48 hours, cooled to roomtemperature and concentrated in vacuo. The crude material was purifiedby reverse phase HPLC (Column: Waters Sunfire C18 19×100 mm, 5 μm;Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA inMeCN (v/v); 95.0% H₂O/5.0% MeCN linear to 0% H₂O/100% MeCN in 7.0 min,HOLD at 0% H₂O/100% MeCN to 8.5 min. Flow: 25 mL/min) to afford thetitle compound (4.9 mg, 11% yield). MS (ES+) 331.1 (M+H)⁺. Retentiontime=2.71 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobilephase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN(v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95A:B to 5.0 min. Flow: 2 mL/min).

Example 1266-Chloro-5-(4-((1R,3R)-3-hydroxycyclobutyl)phenyl)-1H-indazole-3-carboxylicacid

A suspension of 3-(4-bromophenyl)cyclobutanol (90.6 mg, 0.37 mmol),5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (136 mg, 0.37 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.0 mg,0.018 mmol) and potassium acetate (107 mg, 1.09 mmol) in 1,4-dioxane (1mL) was sealed in a pressure tube and heated to 130° C. for 1 hour. Tothe mixture was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid(100.0 mg, 0.36 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.7 mg,0.018 mmol), 2 N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol)and EtOH (2 mL). The mixture was sealed and heated to 130° C. for 1hour. Water (3 mL) was added to the reaction mixture, followed by 1 NHCl solution to adjust the pH to 2. The layers were separated and theaqueous layer was extracted with EtOAc (3×5 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by reverse phase HPLC (Column: Waters Sunfire C1819×100 mm, 5 μm; Mobile phase A: 0.05% Formic acid in water (v/v);Mobile phase B: 0.05% Formic acid in MeCN (v/v); HOLD at 75.0% H₂O/25.0%MeCN for 1.0 min. 75.0% H₂O/25.0% MeCN linear to 55.0% H₂O/45.0% MeCN in6.75 min, linear to 0% H₂O/100% MeCN to 7.0 min. HOLD at 0% H₂O/100%MeCN from 7.0 to 8.0 min. Flow: 30 ml/min) to afford the title compound(2.4 mg, 2% yield). MS (ES+) 343.1 (M+H)⁺. Retention time=2.42 minutes(Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFAin water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2mL/min).

Example 1276-Chloro-5-(4-(1-(hydroxymethyl)cyclopentyl)phenyl)-1H-indazole-3-carboxylicacid

Step 1 [1-(4-Bromophenyl)cyclopentyl]methanol

Lithium aluminum hydride (827 mg, 20.7 mmol) was stirred in ethyl ether(15 mL) at 0° C. A slurry of 1-(4-bromophenyl)cyclopentanecarboxylicacid (1.86 g, 8.28 mmol) in ethyl ether (30 mL) was added to thesolution of lithium aluminum hydride and the mixture was allowed to warmto room temperature slowly overnight. After 22 hours, the reaction wasquenched with 15% sodium hydroxide until the slurry turned from gray towhite and stopped bubbling. The mixture was stirred vigorously for 30minutes and filtered through Celite®, the filter pad was washed withethyl ether, and the filtrate was concentrated to afford 3 g of acolorless oil, which was purified by flash chromatography (0:1 to 1:1ethyl acetate/heptane, 15 column volumes). The product fractions wereconcentrated in vacuo to afford the title compound as a colorless solid(700 mg, 74% yield). GCMS 254/256 (M)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.45(d, J=8.29 Hz, 2H), 7.20 (d, J=8.29 Hz, 2H), 3.49 (s, 2H), 1.96-2.04 (m,2H), 1.79-1.88 (m, 2H), 1.69-1.78 (m, 4H).

Step 26-Chloro-5-{4-[1-(hydroxymethyl)cyclopentyl]phenyl}-1H-indazole-3-carboxylicacid

A mixture of [1-(4-bromophenyl)cyclopentyl]methanol (700 mg, 2.74 mmol),5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (1030 mg, 3.02 mmol)and potassium acetate (808 mg, 8.23 mmol) was stirred in 1,4-dioxane (6mL) and degassed under high vacuum. The mixture was treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (112 mg, 0.137 mmol) and stirred at 100° C. for1.5 hours. To this mixture was added5-bromo-6-chloro-1H-indazole-3-carboxylic acid (686 mg, 2.49 mmol),ethanol (4 mL), 2 N aqueous potassium carbonate (6 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (108 mg, 0.132 mmol) and stirring was continuedat 100° C. for 4 hours. The mixture was cooled to room temperature,treated with water, adjusted to pH 2 with 1 M HCl, and extracted withethyl acetate (twice). The combined organics were dried over magnesiumsulfate, filtered and concentrated in vacuo to afford 1.6 g viscousbrown oil, which was purified by reversed-phase HPLC (Column: PhenomenexGemini C18 150×21.2 mm 5 μm; Mobile phase A: 0.1% NH₄OH in water (v/v);Mobile phase B: 0.1% NH₄OH in acetonitrile (v/v); Gradient: 95.0%H₂O/5.0% MeCN linear to 95.0% MeCN/5.0% H₂O in 11 min, Flow: 28 mL/mineluting at 9.2 min) to afford the title compound (300 mg, 33% yield). MS(ES+) 371.2 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.09 (s, 1H), 7.77 (s,1H), 7.42 (m, 4H), 3.62 (s, 2H), 1.88-2.13 (m, 4H), 1.77 (m, 4H).

Example 128 6-Chloro-5-(4-morpholinophenyl)-1H-indazole-3-carboxylicacid

Step 1 6-Chloro-5-[4-(morpholin-4-yl)phenyl]-1H-indazole

A mixture of 6-bromo-5-chloro-1H-indazole (72.2 mg, 0.312 mmol),4-(morpholin-4-yl)phenylboronic acid (71 mg, 0.34 mmol), cesiumcarbonate (304 mg, 0.935 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (35.9 mg, 0.031 mmol) was sealed in a microwavevial and purged with nitrogen. The reaction mixture was diluted withtetrahydrofuran (2.5 mL) and water (1 mL) and purged with nitrogen forfive minutes. The reaction mixture was heated to 110° C. for four hours.The reaction mixture was concentrated in vacuo, poured into water andextracted three times with dichloromethane. The combined organic layerswere concentrated in vacuo and purified using flash chromatography(heptanes/ethyl acetate 0:100 to 70:30) to give the title compound (71.9mg). ¹H NMR (500 MHz, CDCl₃) δ 8.07 (br. s., 1H), 7.70 (s, 1H), 7.65 (s,1H), 7.41 (d, J=8.5 Hz, 2H), 7.06 (m, 2H), 4.00-3.88 (m, 4H), 3.28 (m,4H).

Step 2 6-Chloro-3-iodo-5-[4-(morpholin-4-yl)phenyl]-1H-indazole

A solution of 6-chloro-5-[4-(morpholin-4-yl)phenyl]-1H-indazole (72 mg,0.23 mmol) and N,N-dimethylformamide (3 mL) was treated with iodine (91mg, 0.36 mmol) and freshly ground potassium hydroxide (16 mg, 0.26mmol). The reaction mixture was stirred at room temperature for threehours, then treated with additional iodine (50 mg) and potassiumhydroxide (20 mg) and heated to 40° C. for 20 minutes. The reactionmixture was poured into ethyl acetate and saturated aqueous ammoniumchloride. The layers were separated and the organic phase was washedwith 2 N sodium thiosulfate. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. The crude product waspurified by flash chromatography utilizing heptanes/ethyl acetate (100:0to 0:70) to give the title compound (86.7 mg). MS (ES−): 438.0 (M−H)⁻.

Step 3 Ethyl6-chloro-5-[4-(morpholin-4-yl)phenyl]-1H-indazole-3-carboxylate

A Parr shaker bottle was charged with6-chloro-3-iodo-5-[4-(morpholin-4-yl)phenyl]-1H-indazole (86.6 mg, 0.197mmol), sodium acetate (68 mg, 0.83 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (30.0 mg,0.039 mmol), and ethanol (20 mL) and shaken under an atmosphere ofcarbon monoxide (40 psi) at 70° C. for 72 hours. The reaction was cooledand the pressure released. The resultant orange liquid was filtered andwashed with ethanol. The filtrate was concentrated in vacuo to give thecrude product, which was purified by flash chromatography utilizingheptanes/ethyl acetate (0:100 to 60:40) to give the title compound (72mg). MS (ES−) 384.1 (M−H)⁻. ¹H NMR (500 MHz, CD₃OD) δ 8.07 (s, 1H), 7.78(s, 1H), 7.36 (d, J=8.78 Hz, 2H), 7.07 (d, J=8.54 Hz, 2H), 4.48 (q,J=7.07 Hz, 2H), 3.80-3.94 (m, 4H), 3.12-3.27 (m, 4H), 1.44 (t, J=7.07Hz, 3H).

Step 4 6-Chloro-5-[4-(morpholin-4-yl)phenyl]-1H-indazole-3-carboxylicacid

To a solution of ethyl6-chloro-5-[4-(morpholin-4-yl)phenyl]-1H-indazole-3-carboxylate (72 mg,0.19 mmol) in ethanol (2 mL) was added 6 N aqueous sodium hydroxide (0.5mL, 3.0 mmol). The mixture was stirred for three hours at 70° C. Thecooled reaction mixture was neutralized with Dowex acid resinconcentrated in vacuo. The crude product was purified by reverse phasecolumn (water/acetonitrile, 0-40%, 20CV) to give the title compound (21mg).

MS (ES+) 358.1 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (s, 1H), 7.80 (s,1H) 7.29 (d, J=8.59 Hz, 2H) 7.00 (d, J=8.78 Hz, 2H) 3.58-3.82 (m, 4H)3.08-3.20 (m, 4H).

Example 1296-Chloro-5-(4-(phenylethynyl)phenyl)-1H-indazole-3-carboxylic acid

Step 1 Methyl 6-chloro-5-(phenylethynyl)-1H-indazole-3-carboxylate

A mixture of methyl 5-bromo-6-chloro-1H-indazole-3-carboxylate (50 mg,0.17 mmol), triethylamine (0.05 mL, 0.4 mmol),tetrakis(triphenylphosphine)palladium(0) (10.7 mg, 0.009 mmol), copperiodide (3.0 mg, 0.017 mmol) and phenyl acetylene (20 mg, 0.20 mmol) intetrahydrofuran (1.0 mL) was sealed and heated to 120° C. for 16 hours.The cooled reaction mixture was concentrated in vacuo and purified byflash chromatography utilizing heptanes/ethyl acetate (1:1 to 0:1) togive the title compound (20 mg) as a yellow solid. MS (ES−): 309.0(M−H)⁻ Step 2

6-Chloro-5-(phenylethynyl)-1H-indazole-3-carboxylic acid

A solution of methyl6-chloro-5-(phenylethynyl)-1H-indazole-3-carboxylate (20 mg, 0.064 mmol)in methanol (1 mL) was treated with 10 N aqueous sodium hydroxide (2drops) and stirred at room temperature for 16 hours. The reactionmixture was then treated with additional 10 N aqueous sodium hydroxide(2 drops) and heated to 70° C. for two hours. The cooled reactionmixture was evaporated in vacuo, and treated with 1 N citric acid. Theresulting solids were collected by filtration, dried and purified usingprep-HPLC to afford the title compound (1 mg). MS (ES+) 374.9 (M+DMSO)⁺.Retention time: 1.8 min; Xbridge C18 5 μm 4.6×50 mm, 95% H₂O/5% MeCNlinear to 5% H₂O/95% MeCN over 4.0 min, HOLD at 5% H₂O/95% MeCN to 5.0min. (0.03% NH₄OH). Flow: 2.0 mL/min.

Example 1306-Fluoro-5-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-indazole-3-carboxylicacid

Step 15,5-Dimethyl-2-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1,3,2-dioxaborinane

A suspension of 4-(4-bromophenyl)tetrahydro-2H-pyran (1.00 g, 4.15mmol), 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (1.70 g, 4.98mmol), potassium acetate (1.22 g, 12.4 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (169 mg,0.207 mmol) in 1,4-dioxane (10 mL) and stirred for three hours at 120°C. The cooled reaction mixture was poured into water (20 mL) andextracted with ethyl acetate (3×20 mL). The combined organic layers weredried over sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified using silica gel chromatography (100:0 to 75:25,heptanes/ethyl acetate) to give the title compound (740 mg, % yield).GC/MS: 274 (M)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.76 (d, J=7.8 Hz, 2H), 7.23(d, J=7.8 Hz, 2H), 4.09 (dd, J=3.8, 11.1 Hz, 2H), 3.77 (s, 4H), 3.54(dt, J=2.1, 11.6 Hz, 2H), 2.71-2.78 (m, 1H), 1.91-1.74 (m, 4H), 1.03 (s,6H).

Step 2 5-Bromo-6-fluoro-1H-indazole-3-carboxylic acid

A mixture of 6-fluoro-1H-indazole-3-carboxylic acid (4.95 g, 23.8 mmol)and acetic acid (50 mL) was treated with bromine (2.0 mL, 38 mmol)dropwise at room temperature. The reaction mixture was heated to 90° C.and stirred for 16 hours under an atmosphere of nitrogen. The reactionmixture was then exposed to the atmosphere and stirred at 95° C. for 72hours. The resulting solids were collected while the reaction mixturewas still hot and rinsed with diethyl ether two times. The solids weredried at 50° C. under reduced pressure to give the title compound (2.89g). ¹H NMR (500 MHz, DMSO-d₆) δ 8.31 (d, J=6.8 Hz, 1H), 7.71 (d, J=8.8Hz, 1H).

Step 36-Fluoro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indazole-3-carboxylicacid

A mixture of 5-bromo-6-fluoro-1H-indazole-3-carboxylic acid (793 mg,3.06 mmol),5,5-dimethyl-2-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1,3,2-dioxaborinane(839 mg, 3.06 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (175 mg,0.214 mmol) were sealed in a vial and purged with nitrogen. Ethanol (4mL), toluene (2 mL) and aqueous 2 M potassium carbonate (3.67 ml, 7.34mmol) were added and the mixture was heated at 110° C. for 50 minutes.The cooled reaction mixture was poured into dilute HCl and extractedwith ethyl acetate. The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo to give crude material,which was purified using reverse-phase chromatography. The product wascrystallized from isopropanol/hexane to give the title compound as acrystalline solid (110 mg, 11% yield). MS (ES−) 339.1 (M−H)⁻. ¹H NMR(500 MHz, CD₃OD) δ 8.34 (d, J=7.32 Hz, 1H), 7.54 (d, 2H), 7.35 (d, 2H),7.27 (d, J=10.25 Hz, 1H), 4.08 (d, J=10.25 Hz, 2H), 3.61 (td, J=10.98,3.42 Hz, 2H), 2.88 (m, 1H), 1.81-1.90 (m, 4H). m.p.=295° C.

Example 1316-Chloro-5-[4-(1-hydroxycyclobutyl)-3-methoxyphenyl]-1H-indazole-3-carboxylicacid

A sealed tube was charged with1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]cyclobutanol(50 mg, 0.17 mmol), 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (47.4mg, 0.172 mmol), toluene (0.80 mL), THF (0.40 mL), EtOH (0.40 mL), and 2M potassium carbonate (0.40 mL, 0.80 mmol). Nitrogen was then bubbledthrough the mixture for 5 minutes.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.6 mg,0.017 mmol) was added and the tube sealed and heated to 115° C. for 2hours. The reaction was cooled to room temperature, opened, neutralizedwith 1 M NaHSO4, and diluted with ethyl acetate. The layers wereseparated and the aqueous layer was extracted with ethyl acetate (×2).The combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo to provide the crude material (80 mg). 40 mgwas dissolved in DMSO and subjected to reverse phase chromatography toprovide 8 mg (10% yield) of title compound.

MS (ES−) 371.2 (M−H)⁻. Retention time: 3.62 min; Waters Xbridge dC18 5μm 4.6×50 mm, 95% H₂O/5% MeCN linear to 5% H₂O/95% MeCN over 4.0 min,HOLD at 5% H₂O/95% MeCN to 5.0 min. (0.03% NH₄OH). Flow: 2.0 mL/min.

Example 132 6-Chloro-5-(4-methoxyphenyl)-1H-indole-3-sulfonic acid

Step 1 6-Chloro-5-(4-methoxyphenyl)-1H-indole

A mixture of 5-bromo-6-chloro-1H-indole (3.20 g, 13.9 mmol), sodiumcarbonate (3.68 g, 34.7 mmol), and 4-methoxyphenylboronic acid (2.41 g,15.9 mmol) in EtOH (18 mL), toluene (18 mL) and water (18 mL) wasdegassed with N₂ for 15 minutes, treated withtetrakis(triphenylphosphine)palladium(0) (1.20 g, 0.99 mmol) and heatedto 90° C. for 23 hours. The cooled reaction mixture was poured intohalf-saturated NH₄Cl solution (200 mL) and extracted withdichloromethane (3×120 mL). The combined organic layers were dried overNa₂SO₄ and concentrated in vacuo. The resulting dark solid was purifiedby flash chromatography (5-20% EtOAc/heptane) to give the title compound(1.40 g, 39%) as a white solid. MS (ES+) 258.5 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.16 (br. s., 1H), 7.56 (s, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.24(s, 1H), 6.98 (d, J=8.1 Hz, 2H), 6.55 (br. s., 1H), 3.88 (s, 3H).

Step 2 6-Chloro-5-(4-methoxyphenyl)-1H-indole-3-sulfonic acid

A solution of 6-chloro-5-(4-methoxyphenyl)-1H-indole (650 mg, 2.52 mmol)and sulfur trioxide pyridine complex (608 mg, 3.78 mmol) in pyridine(2.52 mL) was heated to 115° C. After 17 hours, the reaction mixture wastreated with additional sulfur trioxide pyridine complex (150 mg, 0.93mmol). After stirring an additional 8 hours at 115° C., the reactionmixture was cooled to room temperature and stirred for an additional 16hours. The reaction mixture was diluted with water (50 mL) and washedwith Et₂O (2×20 mL). The aqueous layer was diluted with MeCN (40 mL) andconcentrated in vacuo. The residue was re-diluted with MeCN (50 mL) andconcentrated to give an off-white semi-solid. The semi-solid wasdissolved in MeOH (15 mL), treated with amberjet 1200(H) ion-exchangeresin (5 g) and stirred at room temperature for 16 hours. The mixturewas filtered through cotton and concentrated. The resulting oil waspurified by reverse phase chromatography (C18 column, 0-40% MeCN/water)to give an oil. This material was dissolved in MeOH (4 mL) and treatedwith sodium methoxide (91 mg). The mixture was stirred at roomtemperature for 15 minutes, and then evaporated under reduced pressureto give a solid glass, which was purified by reverse phasechromatography (C18 column, 0-50% MeCN/H₂O). The fractions containingproduct were combined and concentrated in vacuo. The resulting residuewas suspended in toluene (4 mL) and evaporated. This procedure wasrepeated twice to give a white solid, which was dried under high vacuumat room temperature for 16 hours, then at 80° C. for 2 hours to give thetitle compound (459 mg, 50%) as a white solid. MS (ES+) 359.8 (M+Na)⁺.¹H NMR (500 MHz, DMSO-d₆) δ 11.09 (br. s, 1H), 7.69 (s, 1H), 7.47 (s,1H), 7.37 (d, J=2.44 Hz, 1H), 7.31 (d, J=7.81 Hz, 2H), 7.01 (d, J=8.05Hz, 2H), 3.81 (s, 3H). m.p.=240° C. (dec.)

Example 1336-Chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-indole-3-sulfonic acid

A mixture of 5-bromo-6-chloro-1H-indole (300 mg, 1.30 mmol) and sulfurtrioxide pyridine complex (622 mg, 3.91 mmol) in pyridine (2 mL) wassealed in a pressure tube and heated to 100° C. for 48 hours. Thereaction mixture was concentrated in vacuo to provide5-bromo-6-chloro-1H-indole-3-sulfonic acid as a pyridinium salt, whichwas used directly in the next step without further purification. Amixture of 5-bromo-6-chloro-1H-indole-3-sulfonic acid (100 mg, 0.32mmol), 4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-ol(114 mg, 0.39 mmol), 2 N aqueous potassium carbonate solution (0.64 mL,1.29 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.0 mg,0.016 mmol) in EtOH (5 mL) was sealed and heated to 130° C. for 2 hours.The reaction mixture was diluted with water (10 mL) and washed withEtOAc (2×10 mL). The aqueous layer was concentrated in vacuo andpurified by reversed phase HPLC (Column: Waters Sunfire C18 19×100, 5μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFAin MeCN (v/v); HOLD at 100.0% H₂O/0.0% MeCN for 1.0 min. 100.0% H₂O/0.0%MeCN linear to 5.0% H₂O/95.0% MeCN in 6.75 min, linear to 0% H₂O/100%MeCN to 7.0 min. HOLD at 0% H₂O/100% MeCN from 7.0 to 8.0 min. Flow: 30mL/min.) to provide the title compound (2.3 mg, 2%). MS (ES−) 398.0(M−H)⁺. Retention time=2.28 minutes (Waters Atlantis dC18 4.6×50, 5 μm;Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA inMeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 1346-Chloro-5-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-indole-3-sulfonicacid

A mixture of 5-bromo-6-chloro-1H-indole (300 mg, 1.30 mmol) and sulfurtrioxide pyridine complex (622 mg, 3.91 mmol) in pyridine (2 mL) wassealed in a pressure tube and heated to 100° C. for 48 hours. Thereaction mixture was concentrated in vacuo to provide5-bromo-6-chloro-1H-indole-3-sulfonic acid as a pyridinium salt, whichwas used directly in the next step without further purification. Amixture of 4-(4-bromophenyl)tetrahydropyran (77.0 mg, 0.32 mmol),5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (121 mg, 0.35 mmol),potassium acetate (95.0 mg, 0.97 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.0 mg,0.016 mmol) in 1,4-dioxane (1 mL) was sealed and heated to 100° C. for 1hour. To the mixture was added the above freshly prepared5-bromo-6-chloro-1H-indole-3-sulfonic acid (100 mg, 0.32 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.0 mg,0.016 mmol), 2 N aqueous potassium carbonate solution (0.65 mL, 1.30mmol) and EtOH (5 mL). The reaction mixture was sealed and heated to130° C. for 1 hour. The reaction mixture was diluted with water (10 mL),acidified to pH 2 and washed with EtOAc (10 mL). The aqueous layer wasconcentrated in vacuo and purified by reversed phase HPLC (Column:Waters Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water(v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); HOLD at 100.0% H₂O/0.0%MeCN for 1.0 min. 100.0% H₂O/0.0% MeCN linear to 5.0% H₂O/95.0% MeCN in6.75 min, linear to 0% H₂O/100% MeCN to 7.0 min. HOLD at 0% H₂O/100%MeCN from 7.0 to 8.0 min. Flow: 30 mL/min.) to provide the titlecompound (4.1 mg, 3%). MS (ES−) 390.0 (M−H)⁺. Retention time=2.12minutes (Waters Atlantis dC18 4.6×50, 5 μm; Mobile phase A: 0.05% TFA inwater (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:Blinear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2mL/min).

Example 135 6-fluoro-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylicacid

Step 1 6-fluoro-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carbaldehyde

A glass tube was charged with4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-ol(73.5 mg, 0.25 mmol), 5-bromo-6-fluoro-1H-indole-3-carbaldehyde (60 mg,0.25 mmol), toluene (1.2 mL), THF (0.6 mL), EtOH (0.6 mL), and 2.0 Mpotassium carbonate solution (0.6 mL, 1.2 mmol). Nitrogen was thenbubbled through the mixture for 5 minutes then[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21.5 mg,0.025 mmol) was added. The tube was sealed and heated to 115° C. for 2hours. The reaction was cooled to room temperature, opened, andneutralized with 1.0 M sodium hydrogensulfate then diluted with ethylacetate. The layers were separated and the aqueous extracted with ethylacetate (×2). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. The residue was dissolvedin methylene chloride and methanol, silica was added, and the solventremoved in vacuo. The dry-loaded silica gel was then subjected to flashcolumn chromatography (20% to 100% ethyl acetate/heptane) to provide thetitle compound as a white solid (20 mg, 24%). MS (ES+) 332.3 (M+H). ¹HNMR (500 MHz, DMSO-d₆) δ ppm 12.24 (br. s, 1H) 9.96 (s, 1H) 9.59 (s, 1H)8.36 (s, 1H) 8.19 (d, 1H) 7.67 (d, 2H) 7.58 (d, 2H) 7.46 (d, 1H) 7.33(d, 1H) 7.18 (t, 1H) 6.97 (d, 1H) 6.91 (t, 1H).

Step 2 6-fluoro-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylic acid

A round bottomed flask was charged with6-fluoro-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carbaldehyde (20 mg,0.60 mmol), acetonitrile, (1.0 mL), t-butanol (1.0 mL) and cooled to 0°C. 2-methyl-2-butene (0.49 mL, 4.6 mmol) was then added. In a separateflask, sodium chlorite (102 mg, 1.20 mmol) and NaH₂PO₄ (170 mg, 1.23mmol) were dissolved in water (1 mL) then added to the reaction. Thereaction was sealed and reacted at room temperature for 15 h. Ethylacetate and water were added and the layers were separated. The organiclayer was dried over sodium sulfate, filtered, and concentrated invacuo. Reverse phase HPLC was then used to provide the title compound(8.4 mg, 40%). MS (ES−) 346.1 (M−H)⁻. Retention time: 1.86 min WatersXbridge dC18 5 um 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCNover 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.03% NH₄OH). Flow:2.0 mL/min.

Example 1366-Chloro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1 Methyl6-chloro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indole-3-carboxylate

To a solution of methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(440 mg, 1.37 mmol) and 4-(4-bromophenyl)tetrahydro-2H-pyran (300 mg,1.24 mmol) in toluene (6 mL), ethanol (3 mL), and tetrahydrofuran (3 mL)followed by the addition of 2M potassium carbonate aqueous (3 mL, 6mmol). Nitrogen was bubbled through the reaction for 5 minutes then[1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium-dichloromethanecomplex (120 mg, 0.143 mmol) was added and the reaction heated to 115°C. for 16 hours. The reaction was then cooled to room temperature andfiltered through a pad of celite washing with ethyl acetate. Thefiltrate was concentrated under reduced pressure. The crude product waspurified using the Biotage Isolera One (SNAP 50 g silica gel column) andeluting with a gradient of 0-100% ethyl acetate/heptane yielding 360 mgof the title compound as a solid.

MS (ES+) 370.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) ppm 12.06 (s, 1H), 8.17(s, 1H), 7.92 (s, 1H), 7.65 (s, 1H), 7.27-7.45 (m, 4H), 3.94-4.01 (m,2H), 3.79 (s, 3H), 3.47 (td, 2H), 2.75-2.94 (m, 1H), 1.64-1.82 (m, 4H).

Step 26-Chloro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indole-3-carboxylicacid

To a solution of methyl6-chloro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indole-3-carboxylate(360 mg, 0.973 mmol) in methanol (10 mL) was added sodium hydroxide (1M, 4.0 mL, 4 mmol) and the reaction was heated to 70° C. for 24 hours.The reaction was concentrated under reduced pressure. The crude reactionwas diluted with methanol (9 mL) to which was added additional sodiumhydroxide (1M, 6.0 mL, 6 mmol) and heated to 70° C. for 24 hours. Thereaction was concentrated under reduced pressure and acidified using 1Naqueous hydrochloric acid and extracted three times with ethyl acetate.The combined organic layers were washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The crudematerial was purified using the Biotage Isolera One (SNAP 50 g silicagel column) and eluting with a gradient of 0-20%methanol/dichloromethane yielding 215 mg of the title compound as asolid. To a round bottom flask containing the title compound was addedmethanol (10 mL) and the reaction was heated to reflux. Additionalmethanol (5 mL) was added and the solution was allowed to cool to roomtemperature and stirred overnight at room temperature. The resultingprecipitate was filtered and washed with 1 mL of methanol and dried bypulling high vacuum yielding 119 mg of the title compound. MS (ES−)354.0 (M−H)⁻. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.10 (s, 1H), 11.93 (br.d, 1H), 8.07 (d, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.21-7.46 (m, 4H),3.86-4.02 (m, 2H), 3.46 (td, 2H), 2.71-2.93 (m, 1H), 1.60-1.85 (m, 4H).

Example 1376-Chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]-3-methoxyphenyl}-1H-indole-3-carboxylicacid

Step 1 4-Bromo-2-methoxybenzaldehyde

The mixture of 4-bromo-2-fluorobenzaldehyde (6.1 g, 0.03 mol) and sodiummethoxide (1.78 g, 0.033 mol) in dry methanol (60 mL) was stirred atreflux for 16 hours. The methanol was evaporated. The residue waspartitioned between DCM and water. The organic layers were dried oversodium sulfate, concentrated in vacuo to give a yellow solid, which waspurified by silica gel chromatography (Petroleum ether/EtOAc=20:1 to10:1) to give the title compound (6.3 g, 97%) as a light yellow solid.¹H NMR (500 MHz, DMSO-d₆) δ 10.23 (s, 1H), 7.60 (d, 1H), 7.48 (s, 1H),7.28 (d, 1H), 3.94 (s, 3H)

Step 2 (4-Bromo-2-methoxyphenyl)acetonitrile

To a solution of potassium tert-butoxide (6.5 g, 0.058 mol) in1,2-dimethoxyethane (150 mL) was added p-toluenesulfonylmethylisocyanide (5.6 g, 0.029 mol) portionwise at −78° C. Then a solution of4-bromo-2-methoxybenzaldehyde (6.3 g, 0.029 mol) in 1,2-dimethoxyethanewas added dropwise and the reaction mixture was warmed to roomtemperature. The mixture was stirred at room temperature for 1 hour andmethanol (150 mL) was added, then heated to reflux and stirred for 2hours. Solvent was evaporated, and saturated ammonium chloride (100 mL)was added and extracted with ethyl acetate (100 mL×2). The organiclayers were combined, dried over sodium sulfate and concentrated invacuo to give a residue, which was purified by combiflash (Petroleumether/EtOAc=10:1 to 5:1) to give the title compound (5.4 g, 82%) as alight yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, 1H), 7.12 (d,1H), 7.03 (s, 1H), 3.87 (s, 3H), 3.63 (s, 2H)

Step 3 1-(4-Bromo-2-methoxyphenyl)cyclobutanecarbonitrile

To a stirring mixture of (4-bromo-2-methoxyphenyl)acetonitrile (904 mg,4.00 mmol), 1,3-dibromo-propane (880 mg, 4.40 mmol) in dimethylformamide(10 mL) was added sodium hydride (352 mg, 8.80 mmol) at 0° C. Afteraddition, the mixture was stirred at room temperature for 3 hours. Thereaction mixture was quenched with water and extracted withdichloromethane (50 mL×3). The organic phases were combined, dried oversodium sulfate and concentrated in vacuo to give a brown solid. Thesolid was purification by combiflash chromatography (Petroleumether/EtOAc=20:1 to 5:1) to give the title compound (370 mg, 34.8%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.10 (dd, 1H), 7.02 (d, 1H), 7.00(d, 1H), 3.87 (s, 3H), 2.78 (m, 2H), 2.50 (m, 3H), 1.95 (m, 1H)

Step 4 1-(4-Bromo-2-methoxyphenyl)cyclobutanecarboxylic acid

The mixture of 1-(4-bromo-2-methoxyphenyl)cyclobutanecarbonitrile (370mg, 1.04 mmol) in aqueous KOH (80%, 5 mL) and ethylene glycol (5 mL) washeated at 100° C. and stirred for 16 hours. The mixture was added water(20 ml) and acidified by concentrated HCl to pH=1 and extracted withdichloromethane. The combined organic layers was dried over sodiumsulfate, filtered, and concentrated in vacuo to give the title compound(327 mg, 82%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 12.05 (s,1H), 7.19 (d, 1H), 7.13 (s, 1H), 7.12 (d, 1H), 3.72 (s, 3H), 2.59 (m,2H), 2.30 (q, 2H), 2.05 (m, 1H), 1.78 (m, 1H)

Step 5 [1-(4-Bromo-2-methoxyphenyl)cyclobutyl]methanol

To a mixture of 1-(4-bromo-2-methoxyphenyl)cyclobutanecarboxylic acid(320 mg, 1.12 mmol) in dry tetrahydrofuran (10 mL) was addedborane-tetrahydrofuran (0.67 mL, 6.7 mmol) dropwise. The mixture wasstirred at room temperature for 3 hours. The reaction mixture wasquenched by water and extracted with dichloromethane. The organic layerswere combined, dried over sodium sulfate, and concentrated to give thetitle compound (280 mg, 92%) as a colorless oil. ¹H NMR (500 MHz,DMSO-d₆) δ 7.05 (m, 2H), 6.86 (d, 1H), 4.57 (t, 1H), 3.73 (s, 3H), 3.55(d, 2H), 2.05-2.17 (m, 4H), 1.95 (m, 1H), 1.69 (m, 1H).

Step 6 Methyl6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]-3-methoxyphenyl}-1H-indole-3-carboxylate

To a mixture of [1-(4-bromo-2-methoxyphenyl)cyclobutyl]methanol (180 mg,0.660 mmol) in dioxane (10 mL) and water (4 mL) was added methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(213 mg, 0.660 mmol), Pd (dppf)Cl₂ (48 mg, 0.070 mmol) and potassiumcarbonate (273 mg, 2.00 mmol). The reaction mixture was purged withnitrogen for 3 minutes and stirred at 80° C. for 2 hours. The mixturewas extracted with dichloromethane. The organic phases were combined,dried over sodium sulfate, filtered, and concentrated in vacuo to givethe title compound (220 mg, 83%) as a brown solid. It was used for nextstep without further purification.

Step 76-Chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]-3-methoxyphenyl}-1H-indole-3-carboxylicacid

The mixture of methyl6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]-3-methoxyphenyl}-1H-indole-3-carboxylate(220 mg, 0.55 mmol) in aqueous sodium hydroxide (10%, 3 mL) and methanol(5 mL) was stirred at 80° C. for 16 hours. The mixture was acidified byconcentrated HCl to pH-4 and extracted with dichloromethane. The organicphases were combined, dried over sodium sulfate, filtered, andconcentrated in vacuo to give a residue, which was purified by reversephase HPLC to give the title compound (25 mg, 12%) as a white solid. MS(AP+) 368.1 (M−H2O+H)⁺, 408.1 (M+Na)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.03(s, 1H), 7.98 (s, 1H), 7.57 (s, 1H), 7.08 (d, 1H), 6.98 (d, 2H), 3.86(s, 2H), 3.80 (s, 3H), 2.36 (m, 4H), 2.11 (m, 1H), 1.86 (m, 1H)

Example 1386-Chloro-5-[4-(trans-3-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylicacid

Step 1 Methyl6-chloro-5-[4-(trans-3-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylate

To a solution of trans-3-(4-bromophenyl)cyclobutanol (200 mg, 0.88 mmol)in toluene/ethanol (4 mL, v/v=1/1) was added methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(296 mg, 0.968 mmol), potassium carbonate (360 mg, 2.64 mmol), water (1mL) and Pd(dppf)C12 (46 mg, 0.06 mmol) under nitrogen. The mixture wasstirred at 110° C. for 2 hours. The mixture was diluted with ethylacetate and water. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried and concentrated. The residue was purified by silicagel combiflash to give the title compound (190 mg, 61%) as a lightyellow solid. ¹H NMR (500 MHz, CD₃OD) δ 8.02 (s, 1H), 8.01 (s, 1H), 7.60(s, 1H), 7.40-7.35 (m, 4H), 4.52 (m, 1H), 3.88 (s, 3H), 3.66 (m, 1H),2.57-2.44 (m, 4H).

Step 26-chloro-5-[4-(trans-3-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylicacid

To a solution of methyl6-chloro-5-[4-(trans-3-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylate(290 mg, 0.82 mmol) in methanol/water (20 mL, v/v=1/1) was added sodiumhydroxide (326 mg, 8.17 mmol). The mixture was stirred at 90° C. for 5hours. The mixture was then acidified with 1 M HCl to pH˜5. Theresulting suspension was extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over sodium sulfate andconcentrated. The residue was purified by reverse phase HPLC to give thetitle compound (150 mg, 54%) as a white solid. MS (AP+) 342.0 (M+H)⁺: ¹HNMR (500 MHz, CD₃OD) δ 8.03 (s, 1H), 8.02 (s, 1H), 7.59 (s, 1H), 7.41(d, 2H), 7.34 (d, 2H), 4.53-4.50 (m, 1H), 3.67-3.65 (m, 1H), 2.55-2.43(m, 4H).

Example 1396-Chloro-5-(4-(2-hydroxyethoxy)phenyl)-1H-indole-3-carboxylic acid

Step 1 Methyl6-chloro-5-(4-(2-hydroxyethoxy)phenyl)-1H-indole-3-carboxylate

A mixture of methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (5.2 g,18.0 mmol), 2-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy)ethanol(5.7 g, 22.8 mmol), PdCl₂(dppf) (0.54 g, 0.72 mmol), 2 M aqueoussolution of potassium carbonate (27 ml, 54.0 mmol), ethanol (30 ml), andtoluene (90 ml) was stirred in a closed bottle at 80° C. for 2 hours andat 90° C. for 2 more hours. The reaction mixture was cooled to roomtemperature, ethyl acetate (50 ml) was added, and the mixture wasfiltered through a pad of Celite. The organic phase of the mother liquorwas separated. Filter cake was washed with 10% of methanol in THF andthis wash was combined with the first organic extract. The combinedorganic solution was dried over anhydrous magnesium sulfate and loadedon silica gel. Chromatography on a silica gel column, eluting with agradient from 40% to 90% of ethyl acetate in heptanes to give the titlecompound (6.15 g, 98%). MS (ES+) 346.0 (M+1)⁺. ¹H NMR (CDCl₃): δ 8.74(br. s, 1H), 8.13 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.56 (s, 1H), 7.44(d, J=8.5 Hz, 2H), 7.02 (d, J=8.5 Hz, 2H), 4.18 (t, 2H), 4.02 (t, 2H),3.92 (s, 3H).

Step 2 6-Chloro-5-(4-(2-hydroxyethoxy)phenyl)-1H-indole-3-carboxylicacid

A mixture of methyl6-chloro-5-(4-(2-hydroxyethoxy)phenyl)-1H-indole-3-carboxylate (6.15 g,17.8 mmol), 300 ml of methanol (300 ml), and 1 M aqueous sodiumhydroxide (100 ml, 100 mmol) was stirred at 75° C. for 18 hours.Additional 30 ml of 1 M aq. sodium hydroxide added and the reaction wasstirred at 75° C. for 5 more hours. The reaction was concentrated at 45°C. to remove most of methanol, the residue was diluted with water (100ml) and washed with methyl t-butyl ether (2×100 ml). The aqueous phasewas acidified with 37% hydrochloric acid (14 ml) and extracted withethyl acetate (250 ml). The organic extract was washed with brine (2×100ml), and dried over anhydrous magnesium sulfate. The obtained yellowsolution was stirred with activated carbon (5 g) and silica gel (10 g)for 3 hours at room temperature. The suspension was filtered through apad of silica gel and concentrated to obtain crude target product (3.7g). The obtained material was dissolved in ethyl acetate (220 ml) afterheating at 85° C. for 2 hours. To the stirred clear solution was addedin drops heptane (40 ml) at the same temperature (the solution becamecloudy at this point). The mixture was cooled under stirring to roomtemperature in 1.5 hours and stirred for 2.5 days. The precipitate wasfiltered off and dried in high vacuum at 55° C. to obtain the titlecompound (2.5 g, 44%).

MS (ES−) 330.1 (M−H)⁻. ¹H NMR (DMSO-d₆): δ 12.11 (br. s, 1H), 11.93 (br.s, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.34 (d, J=8.8 Hz,2H), 7.02 (d, J=8.8 Hz, 2H), 4.89 (br. s, 1H), 4.04 (t, J=4.9 Hz, 2H),3.75 (t, J=4.9 Hz, 2H).

Example 1406-chloro-5-{4-[2-(1H-1,2,4-triazol-1-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid

A vial was charged with 1-tert-butyl 3-methyl6-chloro-5-(4-hydroxyphenyl)-1H-indole-1,3-dicarboxylate (30 mg, 0.075mmol), 1-(2-chloroethyl)-1H-1,2,4-triazole (15 mg, 0.12 mmol) andtetrahydrofuran (1 mL). Cesium carbonate (64 mg, 0.18 mmol) was thenadded and the vial was sealed and stirred at room temperature for 3hours then heated to 70° C. for 18 h. The reaction was filtered and thefiltrate was concentrated in vacuo. Methanol (1 mL) and 1.0 M sodiumhydroxide (0.3 mL, 0.3 mmol) were added and the reaction stirred for 18h at 70° C. The reaction was then concentrated in vacuo and purified byreverse phase HPLC to provide 1 mg of the title compound. MS (ES⁺) 383.1(M+H)⁺. Retention time=2.38 minutes (Waters Atlantis dC18 4.6×50, 5 μm;Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA inMeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at5:95 A:B to 5.0 min. Flow: 2 mL/min).

Example 1414,6-difluoro-5-(4-(1-(hydroxymethyl)cyclobutyl)phenyl)-1H-indole-3-carboxylicacid

Step 14,6-difluoro-5-(4-(1-(hydroxymethyl)cyclobutyl)phenyl)-1H-indole-3-carbaldehyde

[1-(4-bromophenyl)cyclobutyl]methanol, prepared as described in Example72 (steps 1 and 2), is treated with5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde, prepared as described inExample 6 (steps 1-4), in a manner similar as described in Example 6step 5 to provide the title compound.

Step 24,6-difluoro-5-(4-(1-(hydroxymethyl)cyclobutyl)phenyl)-1H-indole-3-carboxylicacid

The title compound is prepared by treating4,6-difluoro-5-(4-(1-(hydroxymethyl)cyclobutyl)phenyl)-1H-indole-3-carbaldehydein a similar manner as described in Example 6 (step 6) to provide thetitle compound.

Example 1426-chloro-5-{3-fluoro-4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylicacid

This was prepared by the method of example 137, steps 3-7, but startingwith commercially available (4-bromo-2-fluorophenyl)acetonitrile to givethe title compound. MS (ES−) 372.4 (M−H)⁻. 1H NMR (400 MHz, DMSO-d6) δppm 12.16 (s, 1H) 11.97 (br. s., 1H) 8.10 (d, 1H) 7.96 (s, 1H) 7.65 (s,1H) 7.17 (m, 3H) 4.85 (t, 1H) 3.66 (d, 2H) 2.33 (m, 4H) 2.06 (m, 1H)1.83 (m, 1H).

Example 1436-fluoro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylicacid

This was prepared by the method of example 37, steps 1-4, but startingwith [1-(4-bromophenyl)cyclobutyl]methanol and5-bromo-6-fluoro-1H-indole to give the title compound. MS (ES+) 340.1(M+H)⁺. 1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 11.88 (d, 1H),7.98-8.05 (m, 2H), 7.45 (dd, 2H), 7.35 (d, 1H), 7.18-7.25 (m, 2H), 4.77(t, 1H), 3.54 (d, 2H), 2.13-2.32 (m, 4H), 1.93-2.08 (m, 1H), 1.70-1.86(m, 1H).

Example 1446-chloro-5-[(2S)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1H-indole-3-carboxylicacid

This was prepared by the method of Example 37, Steps 3-4, using[(2S)-6-bromo-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.54 g, 2.05mmol) (which can be prepared as in Biorg. Med. Chem. 2007, 15, 4048.) togive the title compound. MS (ES+) 360.1 (M+H)⁺. 1H NMR (400 MHz, CD₃OD)δ 7.97 (s, 2H), 7.54 (s, 1H), 6.90 (m, 3H), 4.35 (dd, 1H), 4.22 (m, 1H),4.09 (dd, 1H), 3.80 (m, 2H).

Example 1456-chloro-5-[(2S)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1H-indole-3-carboxylicacid

Was prepared in a manner similarly described in Example 6, Steps 5-6with1-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]cyclobutanoland 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde to give the titlecompound. MS (ES+) 396.0 (M+Na)+¹HNMR (400 MHz, DMSO-d6) δ ppm 8.08 (s,1H) 7.36 (d, 1H) 7.26 (d, 1H) 7.01 (s, 1H) 6.96 (d, 1H) 5.07 (s, 1H)3.08 (s, 3H) 2.59 (m, 2H) 2.21 (m, 2H) 2.01 (m, 1H) 1.66 (m, 1H).

Example 1466-chloro-5-[4-(trans-3-hydroxycyclobutyl)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

Step 1 4-bromo-2-methoxybenzaldehyde

A mixture of 4-bromo-2-fluorobenzaldehyde (25.0 g, 0.123 mol) and sodiummethoxide (13.99 g, 0.2600 mol) in dry methanol (250 mL) was stirred atreflux temperature for 16 hours. The mixture was concentrated and theresidue was partitioned between dichloromethane (500 mL) and water (250mL). The organic layers were combined and dried over sodium sulfate thenconcentrated in vacuo to provide the title compound as yellow solid (25g, 94.5%).

Step 2 4-bromo-1-ethenyl-2-methoxybenzene

To a suspension of Methyltriphenylphosphonium bromide (5.7 g, 15.6 mmol)in anhydrous toluene (7 mL) was added Lithium bis(trimethylsilyl)amide(14.28 mL, 1M tetrahydrofuran) at 0° C. After addition, the mixture wasstirred at room temperature for 1 h, then cooled to 0° C. and a solutionof 4-bromo-2-fluorobenzaldehyde (2.0 g, 9.3 mmol) in anhydrous toluene(33 mL) was added dropwise. The mixture was stirred at room temperatureovernight. The mixture was cooled to 0° C. and aqueous ammonium chloride(12 mL) was added. The mixture was extracted with ethyl acetate (300 mL)and the organic layers were washed with brine (300 mL), dried oversodium sulfate and filtered, the filtrate was concentrated in vacuum togive crude product (4 g), which was purified via silica gelchromatography to give the title compound (1.4 g, 42%) as an oil.

Step 3 3-(4-bromo-2-methoxyphenyl)-2,2-dichlorocyclobutanone

To a suspension of activated Zn—Cu complex (1.4 g, 19 mmol) and4-bromo-1-ethenyl-2-methoxybenzene (2.700 g, 12.67 mmol) in drytetrahydrofuran (30 mL) was added dropwise through addition funnel asolution of thrichloroacetic chloride (2.11 g, 19.0 mmol) and phosphorylchloride (11.7 ml, 12.7 mmol) in tetrahydrofuran (20 mL) during 2 hr atrefluxing temperature. Then the mixture was stirred overnight underrefluxing temperature. The mixture was cooled to room temperature andfiltered. The filtrate was combined with ethyl acetate (100 mL), thecombined solution was concentrated to give the title compound (1.45 g,35%) which was used into next step without further purification.

Step 4 3-(4-bromo-2-methoxyphenyl)cyclobutanone

In a 50 mL round-bottom flask equipped with a reflux condenser is placed3-(4-bromo-2-methoxyphenyl)-2,2-dichlorocyclobutanone (300 mg, 1.08mmol) and activated zinc (280 mg, 4.30 mmol), in a saturated methanolicammonium chloride solution (2 ml), the suspension is refluxed for 6 hr,then cooled to 23° C. and filtered through celite and rinsed withpetroleum ether (10 mL), and organics are rinsed with water (10 mL), satsodium bicarbonate (10 mL) and brine (10 ml), dried over sodium sulfateand concentrated under reduced pressure, the crude material was purifiedby silica gel chromatography to give the title compound (200 mg, 85%).

Step 5 cis-3-(4-bromo-2-methoxyphenyl)cyclobutanol

Sodium borohydride (0.25 g, 6.75 mmol) was added to a solution of3-(4-bromo-2-methoxyphenyl)cyclobutanone (1.87 g, 7.3 mmol) intetrahydrofuran (70 mL) at 0° C., the reaction was stirred roomtemperature 1 hr, extracted with 1:1 solution of ethyl acetate inheptane, the organic layers was washed with brine (50 mL), dried oversodium sulfate, and concentrated to give the title compound (1.34 g,77.18%).

Step 6 trans-3-(4-bromo-2-methoxyphenyl)cyclobutanol

To a solution of triphenylphosphine (142.7 mg, 0.546 mmol) intetrahydrofuran (2 mL) was added diisopropyl azodicarboxylate (11 mg,0.54 mmol), and the resulting mixture was stirred at room temperaturefor 30 min. The mixture was cooled to −50° C. andcis-3-(4-bromo-2-methoxyphenyl)cyclobutanol (100 mg, 0.389 mmol) intetrahydrofuran (0.5 mL) was added. The reaction was stirred for 20 min,followed by addition of solid 4-nitrobenzoic acid (90.97 mg, 0.546mmol), the resulting mixture was warmed to room temperature and allowedto stir at room temperature for 15 hr. The reaction was then cooled to0° C., to which was added sodium hydroxide (5 mL, 0.5 M in methanol).After 40 min the reaction was quenched with sat. ammonium chloride (5mL), and diluted with ethyl acetate (15 mL). The organic layer wasseparated, dried over sodium sulfate, filtered and evaporated to drynessto give the title compound (78 mg, 54%) as an oil.

Step 76-chloro-5-[4-(trans-3-hydroxycyclobutyl)-3-methoxyphenyl]-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 37, Steps 3-4 withtrans-3-(4-bromo-2-methoxyphenyl)cyclobutanol to give the titlecompound. MS (ES+) 396.0 (M+Na)⁺1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H)7.36 (d, 1H) 7.26 (d, 1H) 7.01 (s, 1H) 6.96 (d, 1H) 5.07 (s, 1H) 3.08(s, 3H) 2.59 (m, 2H) 2.21 (m, 2H) 2.01 (m, 1H) 1.66 (m, 1H).

Example 1476-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-N-(methylsulfonyl)-1H-indole-3-carboxamide

To a mixture of6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carbaldehyde (40mg, 0.123 mmol), Bis(tert-butylcarbonyloxy)iodobenzene (104 mg, 0.256mmol) in isopropyl acetate (2 mL) was added methanesulfonamide (12 mg,0.126 mmol). After stirring 5 minutes,Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] (5 mg,0.007 mmol) was added and heated to 80° C. overnight. The mixture wasconcentrated to give a crude residue, which was purified by preparativeHPLC to afford the title compound (6.6 mg, 13%) as a yellow solid.

MS (ES+) 419.2 (M+H)⁺. 1H NMR (400 MHz, CD3OD) δ 8.18 (s, 2H), 8.17 (s,2H), 7.63 (s, 1H), 7.60 (d, 2H), 7.47 (d, 2H), 3.39 (s, 3H), 2.62 (m,2H), 2.42 (m, 2H), 2.06 (m, 1H), 1.78 (m, 1H).

Example 1486-chloro-5-[3-hydroxy-4-(1-hydroxy-2-methylpropan-2-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1 5-bromo-2-(1-hydroxy-2-methylpropan-2-yl)phenol

To a solution of 2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol (300mg, 1.16 mmol) in dichloromethane (5 mL) was added dropwise borontribromide (580 mg, 2.32 mmol) at −78° C. under nitrogen. The reactionmixture was warmed to room temperature and stirred for 30 minutes. Thereaction was quenched with water (10 mL) and extracted withdichloromethane (20 mL). The organic layer was washed with aq. sodiumbicaronate (20 mL), brine (20 mL), dried over sodium sulfate, filteredand concentrated to give a crude residue, which was purified by flashchromatography to give the title compound (90 mg, 32%) as a white solid.

Step 26-chloro-5-[3-hydroxy-4-(1-hydroxy-2-methylpropan-2-yl)phenyl]-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 37, Steps 3-4 with5-bromo-2-(1-hydroxy-2-methylpropan-2-yl)phenol to give the titlecompound. MS (ES+) 360.1 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 7.99 (s, 1H),7.96 (s, 1H), 7.54 (s, 1H), 7.25 (d, 1H), 6.86 (d, 2H), 3.85 (s, 2H),1.41 (s, 6H).

Example 149chloro-5-[5-(3-hydroxypyrrolidin-1-yl)-6-methoxypyridin-2-yl]-1H-indole-3-carboxylicacid

Step 1 3-bromo-6-chloro-2-methoxypyridine

To a solution of 3-bromo-2,6-dichloropyridine (3.00 g, 13.2 mmol) inacetonitrile (20 mL) was added sodium methoxide (methanol solution, 4.83mol/L, 3.0 mL) dropwise at 0° C. The mixture was stirred at roomtemperature over night. To the mixture was added 30 mL of water, and theorganic was evaporated. The resulting suspension was filtered, and thepad was washed with water for several times. The pad was dried underreduce pressure to give title compound (2.74 g, 93.2%) as white solid.

Step 2 1-(6-chloro-2-methoxypyridin-3-yl)pyrrolidin-3-ol

A vial was charged 3-bromo-6-chloro-2-methoxypyridine (0.50 g, 2.2mmol), pyrrolidin-3-ol (0.39 g, 4.5 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.10 g, 0.10 mmol), Xantphos(0.13 g, 0.20 mmol), sodium tertbutoxide (0.32 g, 3.4 mmol) and toluene(5 mL). The mixture was purged with nitrogen then sealed. The mixturewas heated to 100° C. overnight. The mixture was cooled to roomtemperature, filtered and diluted with 15 mL of water. The solution wasextracted with ethyl acetate (10 mL×3). The organic layers werecombined, dried over sodium sulfate, filtered and concentrated. Theresulting residue was purified by silica gel chromatography to give thetitle compound (29.5 mg, 5.7%) as light brown solid.

Step 36-chloro-5-[5-(3-hydroxypyrrolidin-1-yl)-6-methoxypyridin-2-yl]-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 37, Steps 3-4 with1-(6-chloro-2-methoxypyridin-3-yl)pyrrolidin-3-ol to give the titlecompound. MS (ES+) 388.1 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H),8.25 (s, 1H), 7.98 (s, 1H), 7.11 (d, 1H) 6.98 (d, 1H), 4.48 (m, 1H),3.99 (s, 3H), 3.70 (m, 1H), 3.60 (m, 1H), 3.38 (m, 2H), 2.15 (m, 1H),1.96 (m, 1H).

Examples 150 and 1516-fluoro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylic acid

Step 1 1-(4-bromophenyl)-4-chlorobutan-1-ol

To a solution of 1-(4-bromophenyl)-4-chlorobutan-1-one (1.00 g, 3.83mmol) in methanol (20 mL) was added sodium borohydride (260 mg, 7.66mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. 1 M HCl wasadded and the mixture was stirred for 15 minutes. Solvents were removedand the residue was extracted with ethyl acetate (10 mL×2). The combinedorganic layer were washed with brine, dried and concentrated to givetarget compound (1 g, 99%) as a light yellow oil.

Step 2 2-(4-bromophenyl)tetrahydrofuran

To a solution of 1-(4-bromophenyl)-4-chlorobutan-1-ol (1.0 g, 3.8 mmol)in tetrahydrofuran (20 mL) was added sodium hydroxide (110 mg, 4.56mmol) at 0° C. After being stirred for 2 hours, the reaction mixture wasquenched with water, brought to pH=6 with 1 M HCl aqueous, and extractedwith ethyl acetate. The organic was washed with brine, dried over sodiumsulfate, filtered and concentrated to give the target compound (910 mg,100%) as a yellow solid.

Step 3Racemic-6-fluoro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylicacid

This was prepared in a similar manner to example 4, steps 1-3 with2-(4-bromophenyl)tetrahydrofuran to provide the title compound.

Step 46-fluoro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylicacid—Isomer 16-fluoro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylicacid—Isomer 2

Racemic6-fluoro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylic acidwas subjected to preparative SFC (Column: AD(250×30 mm, 5 um); Mobilephase: 35% MEOH 50 ML/MIN; Wavelength: 220 nm). Peak 1 was isolated asIsomer 1 (Example 150), Retention time=2.22 min; Column: Chiralpak AD-3150×4.6 mm I.D., 3 um Mobile phase: methanol (0.05% DEA) in CO2 from 5%to 40% Flow rate: 2.5 mL/min Wavelength: 220 nm; MS (ES+) 326.0 (M+H)+.1H NMR (400 MHz, Methanol-d4) δ ppm 8.12 (d, 1H) 7.97 (s, 1H) 7.54 (d,2H) 7.42 (d, 2H) 7.25 (d, 1H) 4.94 (t, 1H) 4.13 (q, 1H) 3.95 (q, 1H)2.39 (m, 1H) 2.08 (m, 2H) 1.86 (m, 1H). Peak 2 was isolated as Isomer 2(Example 151), Retention time=2.55 min; Column: Chiralpak AD-3 150×4.6mm I.D., 3 um Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%Flow rate: 2.5 mL/min Wavelength: 220 nm; MS (ES+) 326.1 (M+H)+. 1H NMR(400 MHz, METHANOL-d4) δ ppm 8.12 (d, 1H) 7.97 (s, 1H) 7.54 (d, 2H) 7.42(d, 2H) 7.25 (d, 1H) 4.94 (t, 1H) 4.13 (q, 1H) 3.95 (q, 1H) 2.39 (m, 1H)2.07 (m, 2H) 1.86 (m, 1H).

Examples 152 and 1534,6-difluoro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1Racemic-4,6-difluoro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylicacid

This was prepared in a manner similarly described in Example 6, Steps5-6 with 2-(4-bromophenyl)tetrahydrofuran and5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde to give the titlecompound.

Step 24,6-difluoro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylicacid Isomer 14,6-difluoro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylicacid Isomer 2

Racemic-4,6-difluoro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylicacid was subjected to separation by preparative SFC (Column: OJ (250MM*30 MM, 5 UM); Mobile phase: 30% MEOH NH3H2O 60 ML/MIN 3; Wavelength:220 nm) Peak 1 was isolated and arbitrarily called4,6-difluoro-5-{4-[(2S)-tetrahydrofuran-2-yl]phenyl}-1H-indole-3-carboxylicacid. Peak 1 was isolated as Isomer 1 (Example 152) Retention time=8.43min; Column: Chiralcel OJ-H 250×4.6 mm I.D., 5 um Mobile phase: methanol(0.05% DEA) in CO2 from 5% to 40% Flow rate: 2.5 mL/min Wavelength: 220nm. MS (ES+) 343.8 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H) 7.42(m, 5H) 7.25 (d, 1H) 4.88 (t, 1H) 4.03 (q, 1H) 3.85 (q, 1H) 2.35 (m, 1H)1.99 (m, 2H) 1.75 (m, 1H). Peak 2 was isolated as Isomer 2 (Example153), Retention time=8.86 min; Column: Chiralcel OJ-H 250×4.6 mm I.D., 5um Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40% Flow rate:2.5 mL/min Wavelength: 220 nm.

MS (ES+) 343.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H) 7.41 (m,4H) 7.24 (d, 1H) 4.87 (t, 1H) 4.02 (q, 1H) 3.84 (q, 1H) 2.35 (dq, 1H)1.97 (m, 2H) 1.73 (m, 1H).

Examples 154 and 1556-chloro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylic acidIsomer 16-chloro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylic acidIsomer 2

This was prepared in a manner similar to example 37, steps 3-4 with2-(4-bromophenyl)tetrahydrofuran and subjected to preparative chiralSFC. Column: Chiral Tech IC-H 250 mm×21.2 mm 5u. Isocratic 70% CO2 30%Methanol. Detection 210 nM. Flow: 80.0 mL/min, backpressure 120 Bar.Peak 1 was isolated as Isomer 1 (Example 154); Retention time=6.994;Chiral Tech IC-H 250 mm×4.6 mm 5u. Gradient Mobile Phase A: CO2 B:Methanol Time: 0 min: 95% A 5% B. 1 min: 95% A 5% B 9 min: 40% A 60% B.9.5 min: 40% A, 60% B 10.0 min: 95% A 5% B. Detection: 210 nm.Backpressure 120 Bar. MS (ES−): 340.2 (M−H)⁻¹H NMR (500 MHz, DMSO-d₆)ppm 11.98-12.17 (br. s, 1H) 11.94 (br. s, 1H) 8.07 (s, 1H) 7.94 (s, 1H)7.62 (s, 1H) 7.39 (s, 4H) 4.86 (t, 1H) 3.97-4.04 (m, 1H) 3.83 (dt, 1H)2.33 (ddt, 1H) 1.89-2.02 (m, 2H) 1.73 (dq, 1H). Peak 2 was isolated asIsomer 2 (Example 155), Retention time=7.530; Chiral Tech IC-H 250mm×4.6 mm 5u. Gradient Mobile Phase A: CO2 B: Methanol Time: 0 min: 95%A 5% B. 1 min: 95% A 5% B 9 min: 40% A 60% B. 9.5 min: 40% A, 60% B 10.0min: 95% A 5% B. Detection: 210 nm. Backpressure 120 Bar. MS (ES−):340.2 (M−H)⁻. ¹H NMR (500 MHz, DMSO-d₆) ppm 11.47-12.13 (m, 1H) 8.06 (s,1H) 7.94 (s, 1H) 7.62 (s, 1H) 7.39 (s, 4H) 4.86 (t, 1H) 4.01 (m, 1H)3.83 (dt, 1H) 2.29-2.37 (m, 1H) 1.93-2.00 (m, 2H) 1.73 (dq, 1H)

Example 1566-chloro-5-(4-(2-(oxetan-3-yl)ethoxy)phenyl)-1H-indole-3-carboxylic acid

Step 1 1-bromo-4-(2-bromoethoxy)benzene

To a suspension of 4-bromophenol (2.00 g, 11.6 mmol) in water (20 mL)was added 1,2-dibromoethane (5.40 g, 28.8 mmol) and sodium hydroxide(0.700 g, 17.5 mmol). Then, the mixture was heated at reflux for 12hours. Water was added, and the mixture was extracted with ethyl acetate(4×30 mL). The combined organic layers were washed with brine (3×20 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure to give the crude product. The crude product was purified byflash chromatography (0-10% ethyl acetate/petroleum ether) to afford thetitle compound (1.8 g, 56%) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) ppm 7.40 (d, 2H), 6.81 (d, 2H), 4.27 (t, 2H),3.64 (t, 2H).

Step 2 diethyl 2-(2-(4-bromophenoxy)ethyl)malonate

To a solution of NaH (0.160 g, 6.68 mmol) in anhydrous tetrahydrofuran(20 mL) was added diethyl malonate (1.07 g, 6.68 mmol) dropwise at 0° C.The resulting colorless solution was stirred at 0° C. for 15 minutes,then at room temperature for 30 minutes before cooling again to 0° C. Asolution of 1-bromo-4-(2-bromoethoxy)benzene (1.70 g, 6.07 mmol) inanhydrous tetrahydrofuran (10 mL) was added over 5 minutes. Theresulting mixture was heated at reflux until complete as judged by TLC.The mixture was cooled to room temperature and carefully quenched withwater and then extracted with ethyl acetate (4×50 mL). The combinedorganic phases were dried over sodium sulfate filtered and concentratedunder reduced pressure to give the title compound (2.5 g) as a colorlessoil which was used in the next step without purification. ¹H NMR (400MHz, CDCl₃) ppm 7.43-7.32 (m, 2H), 6.84-6.68 (m, 2H), 4.32-4.14 (m, 4H),4.01 (m, 2H), 3.64 (m, 1H), 2.43-2.32 (m, 2H), 1.33-1.18 (m, 6H).

Step 3 2-(2-(4-bromophenoxy)ethyl)propane-1,3-diol

To a solution of diethyl 2-(2-(4-bromophenoxy)ethyl)malonate (2.50 g,6.96 mmol) in anhydrous MeOH (15 mL) was added sodium borohydride (1.32g, 34.8 mmol) in portions at 0° C. The reaction mixture was stirred for30 minutes at this temperature. The reaction mixture was then carefullyquenched with water and extracted with ethyl acetate (4×50 mL). Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to give the crude product. The crudeproduct was purified by flash chromatography (ethyl acetate:petroleumether) to deliver the title compound (1.0 g, 52%) as a white solid.

¹H NMR (400 MHz, CDCl₃) ppm 7.38 (d, 2H), 6.78 (d, 2H), 4.04 (t, 2H),3.91-3.82 (m, 2H), 3.81-3.72 (m, 2H), 2.19-2.12 (m, 2H), 2.06-1.97 (m,1H), 1.89-1.84 (m, 2H).

Step 4 4-(4-bromophenoxy)-2-(hydroxymethyl)butyl 4-methylbenzenesulfonate

To a suspension of NaH (0.11 g, 4.58 mmol) in anhydrous tetrahydrofuran(10 mL) was added a solution of2-(2-(4-bromophenoxy)ethyl)propane-1,3-diol (0.63 g, 2.29 mmol) inanhydrous tetrahydrofuran (10 mL) dropwise. The reaction mixture wasstirred at room temperature for 30 minutes. Then, tosyl chloride (0.44g, 2.3 mmol) was added in portions. The reaction mixture was thenstirred at room temperature for 2 hours. The reaction mixture wascarefully quenched with water and extracted with ethyl acetate (4×30mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to give thecrude product, which was purified by flash chromatography (0-35% ethylacetate/petroleum ether) to afford the title compound (0.45 g, 46%) aswhite solid. ¹H NMR (400 MHz, CDCl₃) ppm 7.80 (d, 2H), 7.40-7.30 (m,4H), 6.71 (d, 2H), 4.21-4.09 (m, 2H), 4.00-3.90 (m, 2H), 3.74-3.62 (m,2H), 2.45 (s, 3H), 2.14 (m, 1H), 1.89-1.74 (m, 3H).

Step 5 3-(2-(4-bromophenoxy)ethyl)oxetane

To a solution of 4-(4-bromophenoxy)-2-(hydroxymethyl)butyl4-methylbenzenesulfonate (0.450 g, 1.04 mmol) in anhydroustetrahydrofuran (10 mL) was added n-butyl lithium (0.42 mL, 2.5 M, 1.04mmol) dropwise at 0° C. After complete addition of the n-butyl lithiumsolution, the resulting mixture was heated at reflux overnight. Thereaction was carefully quenched with water and extracted with ethylacetate (5×20 mL). The combined organic layers were dried over sodiumsulfate, filtered and concentrated under reduced pressure to give thecrude product. The crude product was purified by flash chromatography(0-20% ethyl acetate/petroleum ether) to afford the title compound (0.10g, 37%) as a white solid. ¹H NMR (400 MHz, CDCl₃) ppm 7.37 (d, 2H), 6.74(d, 2H), 4.89-4.78 (m, 2H), 4.56-4.45 (m, 2H), 3.94-3.87 (m, 2H),3.30-3.17 (m, 1H), 2.23-2.12 (m, 2H)

Step 66-chloro-5-(4-(2-(oxetan-3-yl)ethoxy)phenyl)-1H-indole-3-carboxylic acid3-(2-(4-bromophenoxy)ethyl)oxetane

This was prepared in a manner similar to Example 37, Steps 3-4 with3-(2-(4-bromophenoxy)ethyl)oxetane to give the title compound. MS (ES+)372.2 (M+H)+. ¹H NMR (400 MHz, DMSO-d₆) ppm 11.91 (br. s., 1H), 8.06 (s,1H), 7.92 (s, 1H), 7.62 (s, 1H), 7.33 (d, 2H), 6.97 (d, 2H), 4.73-4.63(m, 2H), 4.43-4.33 (m, 2H), 4.05-3.95 (m, 2H), 3.20-3.09 (m, 1H),2.15-2.03 (m, 2H).

Example 1576-chloro-5-(4-(3-(oxetan-3-yl)propoxy)phenyl)-1H-indole-3-carboxylicacid

Step 1 1-bromo-4-(3-bromopropoxy)benzene

To a suspension of 4-bromophenol (2.00 g, 11.56 mmol) and potassiumcarbonate (4.79 g, 34.68 mmol) in DMF (12 mL) was added1,3-dibromopropane (7.00 g, 37.3 mmol). The mixture was stirred at roomtemperature overnight. Water was added, and the mixture was extractedwith ethyl acetate (4×30 mL). The combined organic layers were washedwith brine (3×20 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure to give the crude product. The crudeproduct was purified by flash chromatography (0-5% ethylacetate/petroleum ether to afford the title compound (2.35 g, 69%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) ppm 7.39 (d, 2H), 6.80 (d, 2H),4.16-4.01 (m, 2H), 3.55-3.53 (m, 2H), 2.41-2.26 (m, 2H).

Step 26-chloro-5-(4-(3-(oxetan-3-yl)propoxy)phenyl)-1H-indole-3-carboxylicacid

This was prepared in a similar manner to example 156, steps 2-6 with1-bromo-4-(3-bromopropoxy)benzene to provide the title compound. MS(ES+) 386.2 (M+1)⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 11.91 (br. s., 1H),8.06 (s, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 7.34 (d, 2H), 7.02 (d, 2H),4.71-4.64 (m, 2H), 4.32-4.24 (m, 2H), 4.04-3.97 (m, 2H), 3.07-2.96 (m,1H), 1.85-1.75 (m, 2H), 1.74-1.61 (m, 2H).

Example 1586-chloro-5-(4-{[(2R)-1-methoxypropan-2-yl]oxy}phenyl)-1H-indole-3-carboxylicacid

This was synthesized in a manner similar to Example 94, Steps 2-4 with(S)-1-methoxypropan-2-ol to give the title compound, 15 mg. MS (ES+)382.0 (M+Na)⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 12.10 (br. s., 1H), 11.94(br s), 8.08 (d, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.33 (d, 2H), 7.01 (d,2H), 4.67 (m, 1H), 3.51 (dddd, 2H), 3.32 (s, 3H), 1.27 (d, 3H).

Example 1596-chloro-5-(4-{[(2S)-1-methoxypropan-2-yl]oxy}phenyl)-1H-indole-3-carboxylicacid

This was synthesized in a manner similar to Example 94, Steps 2-4 with(R)-1-methoxypropan-2-ol to give the title compound, 20 mg. MS (ES+)360.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 12.10 (br. s., 1H), 11.94(br s), 8.08 (d, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.33 (d, 2H), 7.01 (d,2H), 4.67 (m, 1H), 3.51 (dddd, 2H), 3.32 (s, 3H), 1.27 (d, 3H).

Example 1606-chloro-5-[4-(pyrimidin-2-ylmethoxy)phenyl]-1H-indole-3-carboxylic acid

This was synthesized in a manner similar to Example 94, Steps 2-4 withpyrimidin-2-ylmethanol to give the title compound, 24.0 mg. MS (ES+)380.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) ppm 12.10 (br. s., 1H), 11.94(br s), 8.87 (d, 2H), 8.05 (s, 1H), 7.92 (s, 1H), 7.61 (s, 1H), 7.49 (t,1H), 7.33 (d, 2H), 7.05 (d, 2H), 5.33 (s, 2H).

Example 1616-chloro-5-[6-(3-hydroxypyrrolidin-1-yl)-2-methoxypyridin-3-yl]-1H-indole-3-carboxylicacid

Step 1 1-(5-bromo-6-methoxypyridin-2-yl)pyrrolidin-3-ol

A vial was charged with 3-bromo-6-chloro-2-methoxypyridine (1.00 g, 4.5mmol), rac-pyrrolidin-3-ol (0.59 g, 6.7 mmol), triethylamine (0.91 g,8.9 mmol) and dimethylsulfoxide (4 mL). The mixture was heated to 150°C. for 5 hrs. The mixture was cooled to room temperature and dilutedwith 20 mL of water. The solution was extracted with ethyl acetate (10mL×3). The extracts were combined, dried (sodium sulfate) andconcentrated. The resulting residue was purified through flash columnchromatography (petroleum ether/ethyl acetate=5:1-2:1) to give the titlecompound (0.26 g, 25.3%) as light brown gum.

Step 2 Methyl6-chloro-5-[6-(3-hydroxypyrrolidin-1-yl)-2-methoxypyridin-3-yl]-1H-indole-3-carboxylate

A vial was charged with 1-(5-bromo-6-methoxypyridin-2-yl)pyrrolidin-3-ol(100.0 mg, 0.37 mmol), methyl6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate(176.4 mg, 0.55 mmol), Pd(dppf)C12 (26.8 mg, 0.04 mmol), potassiumcarbonate (152 mg, 1.10 mmol, 2M/L aqueous) and toluene/ethanol (1.5mL/0.5 mL). The mixture was purged with nitrogen for 5 minutes and thensealed. The reaction was heated to 80° C. overnight. The mixture wascooled to room temperature and filtered. The filtrate was diluted withwater (5 mL) and extracted with ethyl acetate (5 mL×3). The organiclayer was dried (sodium sulfate) and concentrated. The resulting residuewas purified through prep. TLC (petroleum ether: ethyl acetate, 2:1) togive the title compound (52.5 mg, 35.7%) as an off-white solid. ¹H NMR(400 MHz, CDCl3) ppm: 8.62 (br. s), 8.05 (s, 1H), 7.89 (d, 1H), 7.50 (s,1H), 7.35 (d, 1H), 6.00 (d, 1H), 4.61 (m, 1H), 3.89 (s, 3H), 3.87 (s,3H), 3.73-3.57 (m, 4H), 2.24-2.05 (m, 2H).

Step 36-chloro-5-[6-(3-hydroxypyrrolidin-1-yl)-2-methoxypyridin-3-yl]-1H-indole-3-carboxylicacid

A vial was charged with methyl6-chloro-5-[6-(3-hydroxypyrrolidin-1-yl)-2-methoxypyridin-3-yl]-1H-indole-3-carboxylate(52.5 mg, 0.130 mmol), NaOH aqueous (2 mL, 2M) and methanol (2 mL). Themixture was heated at 80° C. for 3 hrs. The mixture was cooled to roomtemperature and neutralized with conc. HCl aqueous to pH=6. The mixturewas evaporated to dryness, and the resulting residue was purifiedthrough prep. HPLC to give the title compound (18.9 mg, 37.3%) asoff-white solid.

MS (ES+) 388.1 (M+H)⁺. ¹H NMR (400 MHz, methanol-d₄) ppm: 7.96 (s, 1H),7.92 (s, 1H), 7.51 (s, 1H), 7.29 (d, 1H), 6.02 (d, 1H), 4.60-4.50 (m,1H), 3.83 (s, 3H), 3.68-3.58 (m, 3H), 3.56-3.50 (m, 1H), 2.18 (m, 1H),2.04 (m, 1H).

Example 162 6-chloro-5-[4-(propan-2-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1 6-chloro-5-[4-(propan-2-yl)phenyl]-1H-indole-3-carbaldehyde

A vial was charged with 1 mL of a 0.1M solution of5-bromo-6-chloro-1H-indole-3-carbaldehyde (100 uM) in dioxane, 150 umolof (4-isopropylphenyl)boronic acid solution in dioxane, 200 uL of a 1.0Mcesium carbonate solution in water, and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride), (2 umol, 0.02 eq). The vial was purgedwith nitrogen, sealed and heat to 100° C. for 16 h. The solvent wasevaporated and the vial diluted with ethyl acetate. The organic layerwas collected, washed with brine, dried over magnesium sulfate,filtered, and concentrated in vacuo to give the title compound.

Step 2 6-chloro-5-[4-(propan-2-yl)phenyl]-1H-indole-3-carboxylic acid

A vial was charged with6-chloro-5-[4-(propan-2-yl)phenyl]-1H-indole-3-carbaldehyde, 1 mLacetonitrile, and 500 uL of a 1.0M solution of potassium permanganate inwater. The vial was sealed and heated to 30° C. for 16 hrs. Sodiumbisulfite (72 mg, 1.0 mmol) was then added and the reaction heated to30° C. for 1 hr. The reaction was then filtered, and the solvent removedin vacuo. The residue was then purified by reverse phase prep HPLC togive the title compound. MS(AP−) 312 (M−H)⁻. RT=2.378 Column Xbridge C182.1×50 mm 5 μm, Temperature 50° C. Mobile Phase A=0.05% NH4OH in water.Mobile Phase B=100% acetonitrile. Gradient: Initial 5% B Time 0.00 mins,5% B Time 0.50 mins, 5% B Time 3.40 mins, 100% B Time 4.20 mins, 100% BTime 4.21 mins, 5% B Time 4.70 mins, 5% B Flow rate, 0.8 mL/minInjection volume 2 μL. Agilent 1200 HPLC/1956 MSD/SEDEX 75 ELSDIonization Mode API-ES Polarity Negative.

Example 1636-chloro-5-[3-fluoro-4-(1-hydroxy-2-methylpropan-2-yl)phenyl]-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 142 but substitutingmethyl iodide instead of 1,3-dibromopropane.

MS (ES−): 360.2 (M−H)⁻ ¹H NMR (400 MHz, DMSO-d₆) ppm 12.15 (br. s., 1H)11.98 (br. s., 1H) 8.10 (d, 1H) 7.96 (s, 1H) 7.65 (s, 1H) 7.44 (t, 1H)7.12-7.24 (m, 2H) 4.79 (t, 1H) 3.61 (d, 2H) 1.34 (s, 6H).

Example 1646-chloro-5-{2-fluoro-4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylicacid

Step 1 (1-(4-bromo-3-fluorophenyl)cyclobutyl)methanol

This was prepared in a manner similar to Example 137, steps 2-5 butstarting from (4-bromo-3-fluorophenyl)acetonitrile to prepare the titlecompound.

Step 26-chloro-5-{2-fluoro-4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 137, steps 6-7, butstarting from (1-(4-bromo-3-fluorophenyl)cyclobutyl)methanol to preparethe title compound (49 mg). MS (ES−): 372.4 (M−H)− ¹H NMR (500 MHz,DMSO-d₆) ppm 12.13 (s, 1H), 11.98 (d, 1H), 8.09 (s, 1H), 7.91 (s, 1H),7.64 (s, 1H), 7.29 (d, 1H), 7.03 (dd, 1H), 6.99 (dd, 1H), 4.83 (t, 1H),3.57 (d, 2H), 2.13-2.33 (m, 4H), 1.90-2.10 (m, 1H), 1.57-1.90 (m, 1H).

Example 1656-fluoro-5-{2-fluoro-4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 143 using(1-(4-bromo-3-fluorophenyl)cyclobutyl)methanol obtained from Example164, step 1 to provide the title compound (61 mg). MS (ES−): 356.4(M−H)⁻ ¹H NMR (500 MHz, DMSO-d₆) ppm 12.08 (s, 1H), 11.93 (d, 1H), 8.04(d, 1H), 7.94 (d, 1H), 7.38 (t, 1H), 7.35 (s, 1H), 7.05 (dd, 1H), 7.00(dd, 1H), 4.82 (t, 1H), 3.57 (d, 2H), 2.16-2.29 (m, 4H), 1.94-2.05 (m,1H), 1.74-1.85 (m, 1H).

Example 1664,6-difluoro-5-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1H-indole-3-carboxylicacid

This was prepared in a manner similarly described in Example 6, Steps5-6 with 4-(4-bromophenyl)tetrahydro-2H-pyran and5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde to give the title compound(5.9 mg). MS (ES+): 358.1 (M+H)⁺. retention time=2.73 min; Column:Waters Atlantis dC18 4.6×50 mm, 5 m; Modifier: TFA 0.05%; Gradient: 95%H₂O/5% MeCN linear to 5% H₂O/95% MeCN over 4.0 min, HOLD at 5% H₂O/95%MeCN to 5.0 min; Flow: 2.0 mL/min.

Example 1674,6-difluoro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl)-1H-indole-3-carboxylicacid

Step 1{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}methanol

To a mixture of [1-(4-bromophenyl)cyclobutyl]methanol (241 mg, 1.00mmol) in dioxane (5 mL) and aq.potassium carbonate (1.5 mL, 2.0 M) wasadded 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (381 mg, 1.50mmol), PdCl2dppf (73.1 mg, 0.100 mmol). The reaction mixture was purgedwith nitrogen for 3 minutes and stirred at 80° C. for 4 hours. TLC(petroleum ether/ethyl acetate=1:1) showed the reaction was complete.The mixture was extracted with ethyl acetate (20 mL×3). The organicphases were combined, dried over sodium sulfate, filtered, andconcentrated in vacuo to give a residue, which was purified by silicagel chromatography to give the title compound (106 mg, 36%) as a palesolid. ¹H NMR (400 MHz, CD3OD) δ ppm 7.79 (d, 2H) 7.16 (d, 2H) 3.75 (s,2H) 2.33 (m, 2H) 2.25 (m, 2H) 2.07 (m, 1H) 1.89 (m, 1H) 1.34 (s, 12H)

Step 24,6-difluoro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde

To a mixture of{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}methanol(106 mg, 0.37 mmol) in toluene/ethanol 3:1 (3 mL) and aq.potassiumcarbonate (0.55 mL, 2.0 M) was added5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (96 mg, 0.37 mmol),PdCl2dppf (27 mg, 0.037 mmol). The reaction mixture was purged withnitrogen for 3 minutes and stirred at 130 degree centigrade undermicrowave irradiation for 30 minutes. TLC (petroleum ether/ethylacetate=1:1) showed the reaction was complete. The mixture was extractedwith ethyl acetate (20 mL×3). The organic phases were combined, driedover sodium sulfate, filtered, and concentrated in vacuo to give aresidue, which was purified by combi flash to give compound 15 (34 mg,27%) as a white solid. ¹H NMR (400 MHz, CD3OD) δ ppm 10.03 (s, 1H) 8.14(s, 1H) 7.41 (d, 2H) 7.28 (d, 2H) 7.19 (d, 1H) 3.75 (s, 2H) 2.37 (m, 4H)2.11 (m, 1H) 1.91 (m, 1H)

Step 34,6-difluoro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylicacid

To a solution of4,6-difluoro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde(34 mg, 0.10 mmol) in acetonitrile (5 mL) and tert butanol (5 mL) wasadded 2-methyl-2-butene (700 g, 10.0 mmol). The mixture was cooled to 0°C. with ice bath. The sodium chlorite (273 mg, 3.00 mmol) and sodiumdihydrogenphosphate (360 mg, 3.00 mmol) were dissolved in water (5 mL).The aqueous was added to the organic solution and the mixture wasallowed to warm to room temperature. The reaction mixture was stirred atroom temperature for 48 hours. TLC (petroleum ether/ethyl acetate=1:1)showed the reaction was complete. A solution of sodium sulfite was addedslowly to the stirring mixture. The reaction mixture was allowed to stir1 hour. Then the organics were removed under reduced pressure. Theaqueous layer was extracted with ethyl acetate (20 mL×3). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to give a brown residue. The residue was purifiedby preparative reverse phase HPLC to give the title compound (15 mg,42%) as a white solid. MS (ES+) 380.0 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ8.01 (s, 1H), 7.41 (d, 1H), 7.28 (d, 2H), 7.14 (d, 2H), 3.76 (s, 2H),2.36 (m, 4H), 2.13 (m, 1H), 1.93 (m, 1H).

Example 1686-chloro-5-[4-(tetrahydro-2H-pyran-3-yl)phenyl]-1H-indole-3-carboxylicacid Step 1 5-bromo-3,4-dihydro-2H-pyran

To a solution of 3,4-dihydro-2H-pyran (20.0 g, 0.238 mol) indichloromethane (200 mL) was added bromine (37.8 g, 0.238 mol, 12.2 mL)in dichloromethane (100 mL) at −78° C. dropwise. The mixture was stirredat −78° C. for 2 hours, then at room temperature (30° C.) for 15 hours.Triethylamine (48.0 g, 0.476 mol, 66.0 mL) in dichloromethane (100 mL)was added dropwise at room temperature (30° C.) and then stirred for 5hours. Dichloromethane was removed, and petroleum ether was added, andthe solid was removed by filtration. The filtrate was evaporated, andthe residue was purified by vacuum distillation (80° C., 0.02 mmHg) togive the title compound (6.2 g, 16%) as colorless oil. ¹H NMR (400 MHz,CD3OD) δ ppm 6.60 (s, 1H), 4.00 (t, 2H), 2.40 (t, 2H), 2.00 (m, 2H)

Step 2 5-(4-chlorophenyl)-3,4-dihydro-2H-pyran

A mixture of 5-bromo-3,4-dihydro-2H-pyran (1.0 g, 6.13 mmol),(4-chlorophenyl)boronic acid (1.05 g, 6.74 mmol), potassium carbonate(2.5 g, 18.4 mmol), Pd(dppf)C12 (449 mg, 0.613 mmol), and ethanol/water(2/2 mL) in toluene (10 mL) was stirred at 100° C. for 12 hours. Themixture was filtered, and the filtrate was evaporated and purified bysilica gel chromatography to give the title compound (700 mg, 58.8%) asorange solid. ¹H NMR (400 MHz, CD3OD) δ ppm 7.25 (d, 2H), 7.20 (d, 2H)6.90 (s, 1H), 4.03 (t, 2H), 2.37 (t, 2H), 2.02 (m, 2H)

Step 3 3-(4-chlorophenyl)tetrahydro-2H-pyran

To a solution of 5-(4-chlorophenyl)-3,4-dihydro-2H-pyran (350 mg, 1.80mmol) in ethyl acetate (8 mL) was added platinum oxide (41 mg, 0.18mmol) and the reaction was charged with a hydrogen balloon and stirredat room temperature for 6 hours. The reaction was filtered, and thefiltrate was evaporated to give crude title compound (340 mg, 96.3%) aswhite solid.

Step 46-chloro-5-[4-(tetrahydro-2H-pyran-3-yl)phenyl]-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 37, Steps 3-4 with3-(4-chlorophenyl)tetrahydro-2H-pyran to give the title compound. MS(ES−) 354.1 (M−1)⁻. ¹H NMR (400 MHz, CD3OD) δ ppm 8.03 (s, 1H), 8.00 (s,1H), 7.59 (s, 1H), 7.41 (d, 2H), 7.33 (d, 2H), 4.00 (d, 2H), 3.52 (t,2H), 2.92 (m, 1H), 2.2 (m, 1H), 1.84 (m, 3H).

Examples 169 and 1704,6-difluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1 4-bromo-2-(4-bromophenyl)tetrahydro-2H-pyran

To a solution of 4-bromobenzaldehyde (1.00 g, 5.41 mmol) and3-buten-1-ol (800 mg, 10.8 mmol) in dichloromethane (20 mL) at roomtemperature was added zinc (II) bromide (25 mg, 0.11 mmol) followed by33% hydrobromic acid (2.4 g) in acetic acid (4.9 g, 81 mmol) and stirredat room temperature for 5 hours. Reaction was quenched by aqueous sodiumbicarbonate, then extracted with ethyl acetate, washed with brine, driedover sodium sulfate, filtered and concentrated. The residue was purifiedby silica gel chromatography to give the title compound (1.00 g) whichcontained some of 4-bromobenzaldehyde ¹H NMR (400 MHz, CDCl3) δ ppm 7.49(d, 2H) 7.24 (d, 2H) 5.19 (dd, 1H) 4.25 (m, 1H) 4.12 (m, 1H) 3.60 (m,1H) 2.75 (m, 1H) 2.68 (m, 1H) 2.11 (m, 2H).

Step 2 2-(4-bromophenyl)-3,6-dihydro-2H-pyran

To a solution of 4-bromo-2-(4-bromophenyl)tetrahydro-2H-pyran (320 mg,1.00 mmol) in toluene (5 mL) was added1,8-Diazabicyclo[5.4.0]undec-7-ene (304 mg, 2.00 mmol). The mixture wasstirred at 100° C. for 16 hours. The mixture was then diluted with ethylacetate and water. The organic layer was washed with brine, dried oversodium sulfate, filtered and concentrated. The residue was purified bysilica gel chromatography to give the title compound (150 mg) whichcontained some impurity of 4-bromobenzaldehyde. ¹H NMR (400 MHz, CDCl3)δ ppm 7.48 (d, 2H) 7.30 (d, 2H) 5.92 (m, 1H) 5.82 (m, 1H) 4.52 (dd, 1H)4.36 (m, 2H) 2.27 (m, 2H).

Step 3 2-(4-bromophenyl)tetrahydrofuran

A solution of 2-(4-bromophenyl)-3,6-dihydro-2H-pyran (140 mg, 0.586mmol) in toluene/ethanol (10 mL, v/v=1/1) was charged into ahydrogenation Parr bottle followed by tris(triphenylphosphine)rhodium(I)chloride (55 mg, 0.0586 mmol). The mixture was set up for 45 psi ofhydrogen at 80° C. overnight. The mixture was filtered through celiteand the filtrate was concentrated. The residue was purified by silicagel chromatography to give the title compound (50 mg, 35%) as acolorless oil. ¹H NMR (400 MHz, CDCl3) δ ppm 7.46 (d, 2H) 7.23 (d, 2H)4.29 (d, 1H) 4.13 (m, 1H) 3.60 (t, 1H) 1.95 (m, 1H) 1.81 (d, 1H) 1.60(m, 3H) 1.27 (m, 1H).

Step 46-difluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carbaldehyde

A mixture of5,5-dimethyl-2-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1,3,2-dioxaborinane(444 mg, 1.62 mmol), 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (400mg, 1.54 mmol), potassium carbonate (638 mg, 4.62 mmol) and Pd(dppf)C12(44 mg, 0.06 mmol) in dioxane (4.6 mL) and water (2.3 mL) were stirredat 100° C. for 3 hours. To the reaction was added water (20 mL) andextracted with ethyl acetate (20 mL*3). The combined organic layer waswashed with brine (20 mL), dried over sodium sulfate, filtered andconcentrated to give a crude residue, which was triturated with(petroleum ether/MTPE=1:1) then filtered to give the title compound (400mg, 76.2%) as a red solid and taken on without purification.

Step 5Racemic-4,6-difluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid

To a solution of6-difluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carbaldehyde(400 mg, 1.17 mmol) in acetonitrile (24 mL), tert-butanol (24 mL) and2-methyl-2-butene (15.6 mL) was added a solution of sodium chlorite(1.58 g, 23.4 mmol) and sodium dihydrogen phosphate (3.20 g, 23.4 mmol)in water (24 mL) at ice-bath. The reaction mixture was stirred at roomtemperature for 2 days. A solution of sodium sulfite (4.40 g, 35.1 mmol)in water (10 mL) was added to the mixture and stirred for 30 minutes.The reaction was extracted with ethyl acetate (50 mL×2). The combinedorganic layer was washed with brine (50 mL), dried over sodium sulfate,filtered and concentrated to give a crude residue, which was purified byreverse phase prep-HPLC to give the title compound (80 mg, 19%) as anoff-white solid. MS (ES+) 357.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm12.15 (br. s, 2H), 8.06 (s, 1H) 7.41 (m, 4H) 7.24 (d, 1H) 4.38 (d, 1H)4.05 (d, 1H) 3.55 (m, 1H) 1.86 (m, 2H) 1.56 (m, 4H).

Step 64,6-difluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid Isomer 14,6-difluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid Isomer 2

Racemic4,6-difluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid was subjected to preparative SFC. (Column: OJ (250 MM*30 MM, 5 UM);Mobile phase: 30% MEOH NH3H2O 60 ML/MIN 3; Wavelength: 220 nm). Peak 1was isolated as Isomer 1 (Example 169). Retention time=7.491. Column:Chiralcel OJ-H 250×4.6 mm I.D., 5 um Mobile phase: methanol (0.05% DEA)in CO2 from 5% to 40% Flow rate: 2.35 mL/min Wavelength: 220 nm. MS(ES+) 357.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.15 (br. s, 2H), 8.06(s, 1H) 7.41 (m, 4H) 7.24 (d, 1H) 4.38 (d, 1H) 4.05 (d, 1H) 3.55 (m, 1H)1.86 (m, 2H) 1.56 (m, 4H) Peak 2 was isolated as Isomer 2 (Example 170).Retention time=8.054. Column: Chiralcel OJ-H 250×4.6 mm I.D., 5 umMobile phase: methanol (0.05% DEA) in CO2 from 5% to 40% Flow rate: 2.35mL/min Wavelength: 220 nm. MS (ES+) 379.9 (M+Na)+. 1H NMR (400 MHz,DMSO-d6) δ 12.15 (br. s, 2H), 8.06 (s, 1H) 7.41 (m, 4H) 7.24 (d, 1H)4.38 (d, 1H) 4.05 (d, 1H) 3.56 (m, 1H) 1.86 (m, 2H) 1.53 (m, 4H).

Examples 171 and 1726-fluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid

Step 1Rac-6-fluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid

This was prepared in a manner similarly described in Example 6, Steps5-6 with 2-(4-bromophenyl)tetrahydrofuran and5-bromo-6-fluoro-1H-indole-3-carbaldehyde to give the title compound.

Step 26-fluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid Isomer 16-fluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid Isomer 2

Racemic-6-fluoro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid was subjected to separation by preparative SFC (Column: OJ (250MM*30 MM, 5 UM); Mobile phase: 35% MEOH NH3H2O 55 ML/MIN 2; Wavelength:220 nm) Peak 1 was isolated as Isomer 1 (Example 171), Retention Time:9.44 min; Column: Chiralcel OJ-H 250×4.6 mm I.D., 5 um; Mobile phase:methanol (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.5 mL/minWavelength: 220 nm. MS (ES+) 340.0 (M+Na)+. 1H NMR (400 MHz, DMSO-d6) δppm 8.04 (s, 1H) 8.03 (d, 1H) 7.50 (m, 2H) 7.43 (m, 2H) 7.37 (d, 1H)4.38 (d, 1H) 4.05 (d, 1H) 3.57 (m, 1H) 1.87 (m, 2H) 1.55 (m, 4H).

Peak 2 was isolated as Isomer 2 (Example 172), Retention Time: 9.66 min;Column: Chiralcel OJ-H 250×4.6 mm I.D., 5 um; Mobile phase: methanol(0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.5 mL/min Wavelength: 220nm. MS (ES+) 340.0 (M+Na)⁺. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.04 (s, 1H)8.03 (d, 1H) 7.50 (m, 2H) 7.43 (m, 2H) 7.37 (d, 1H) 4.38 (d, 1H) 4.05(d, 1H) 3.57 (m, 1H) 1.87 (m, 2H) 1.55 (m, 4H).

Example 1736-chloro-5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-1H-indole-3-carboxylicacid

Step 1 5-bromo-6-methoxy-N, N-dimethylpyridin-2-amine

This was prepared in a manner similar to Example 161, step 1 withdimethylamine to give the title compound.

Step 26-chloro-5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 161, steps 2-3 with5-bromo-6-methoxy-N,N-dimethylpyridin-2-amine to give the titlecompound. MS (ES+) 346.1 (M+H)⁺. ¹H NMR (400 MHz, CD3OD) δ 7.94 (d, 1H),7.92 (s, 1H), 7.49 (s, 1H), 7.30 (d, 1H), 6.18 (d, 1H), 3.18 (s, 3H),3.11 (s, 6H).

Alternative Preparation of Example 173

5-bromo-6-chloro-1-(toluene-4-sulfonyl)-1H-indole-3-carboxylic acidmethyl ester

To a solution of 5-bromo-6-chloro-1H-indole-3-carboxylic acid methylester (80.0 g, 277 mmol) in N,N-dimethylformamide (600 mL) at 0° C. wasadded sodium hydride (60% dispersion in oil, 16.6 g, 416 mmol)portion-wise over 20 minutes. The reaction was stirred at 0° C. for 60minutes followed by the addition of 4-methylbenzenesulphonyl chloride(63.4 g, 333 mmol), which was added portion-wise to the stirringsolution. The reaction was allowed to stir for 2 hours at 0° C. and theice bath was removed and the reaction was allowed to warm to roomtemperature and stirred overnight. The reaction was poured into water(1200 mL) and stirred for 12 hours. The suspension was filtered and thefilter cake was washed with a further portion of water (700 mL) thenheptane (2×300 mL), 160 g of crude material was recovered. The materialwas placed in a 3 L round bottom flask and placed on rotorary evaporatedwith a 40° C. bath under vacuum overnight to remove residual water. Thisafforded 116 g of pink solid which was suspended in acetone (600 mL) andheated to reflux for 1 hour, then removed from the heat, cooled to roomtemperature, and stirred for a further hour. The suspension was filteredand the filter cake was washed with acetone (˜500 mL) until the filtratewas colorless. The filter cake was dried to afford desired product(108.7 g, 89% yield). ¹H NMR (CDCl₃, 400 MHz) 5=8.39 (s, 1H) 8.24 (s,1H) 8.11 (s, 1H) 7.82 (d, J=8.59 Hz, 2H) 7.32 (d, J=8.20 Hz, 2H) 3.93(s, 3H) 2.40 (s, 3H); MS (ES+) 441.9 (M+H)⁺.

(6-fluoro-pyridin-2-yl)-dimethyl-amine

Dimethylamine hydrochloride (19.0 g, 91.2 mmol) was added to asuspension of 2,6-difluoropyridine (10.0 g, 86.9 mmol) and potassiumcarbonate (24.4 g, 177 mmol) in acetonitrile (100 mL). The suspensionwas stirred at reflux for 2 h before cooling to room temperature andfiltering through a pad of celite, washing the filter cake withacetonitrile (500 mL). The filtrate was concentrated in vacuo to productdesired product (11.3 g, 93% yield) as an orange oil. ¹H NMR (CDCl₃, 600MHz) 5=7.33-7.66 (m, 1H) 6.28 (dd, J=8.22, 2.35 Hz, 1H) 6.09 (dd,J=7.63, 2.35 Hz, 1H) 3.07 (s, 6H); MS (FID)=140.0 (M)⁺.

(5-bromo-6-fluoro-pyridin-2-yl)-dimethyl-amine

To a solution of Intermediate (6-fluoro-pyridin-2-yl)-dimethyl-amine(12.4 g, 88.4 mmol) in acetonitrile (400 mL) at 0° C. was added asolution of N-bromosuccinimide (7.87 g, 44.2 mmol) in acetonitrile (95mL) dropwise over 15 min. The resulting solution was stirred at 0° C.for 1 hour. Another portion of N-bromosuccinimide (7.87 g, 44.2 mmol) inacetonitrile (95 mL) was subsequently added at 0° C. dropwise over 15min. The solution was slowly warmed to room temperature and stirredovernight. The solution was concentrated in vacuo and diluted withdichloromethane (500 mL). This was washed with water (300 mL) and theaqueous layer back extracted with dichloromethane (3×200 mL), beforedrying over MgSO₄, filtering, and concentrating in vacuo. The materialwas passed through a silica pad, eluting with 0-10% ethyl acetate inheptanes. The organics were concentrated in vacuo to afford desiredmaterial (18.4 g, 95% yield) that solidified upon standing. ¹H NMR(CDCl₃, 400 MHz) 5=7.48-7.67 (m, 1H) 6.21 (dd, J=8.59, 1.56 Hz, 1H) 3.05(s, 6H); MS (FID)=218.0 (M)⁺.

(5-bromo-6-methoxy-pyridin-2-yl)-dimethyl-amine

To a solution of potassium methoxide (25% in methanol, 74.2 mL, 251mmol) was added Intermediate(5-bromo-6-fluoro-pyridin-2-yl)-dimethyl-amine (18.36 g, 83.8 mmol). Thereaction was stirred at reflux for 3 h before cooling to roomtemperature. The contents were poured into a solution of saturatedammonium chloride (500 mL) and this was extracted with ethyl acetate(3×300 mL). The combined organics were washed with brine (250 mL), driedover MgSO₄, filtered, and concentrated in vacuo to afford desiredproduct as an oil that solidified upon standing to give an offwhite/yellow solid (18.3 g, 95% yield). ¹H NMR (CDCl₃, 400 MHz) 5=7.49(d, J=8.59 Hz, 1H) 5.95 (d, J=8.59 Hz, 1H) 3.96 (s, 3H) 3.05 (s, 6H); MS(FID)=230.1 (M)⁺.

6-chloro-5-(6-dimethylamino-2-methoxy-pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-indole-3-carboxylicacid methyl ester

To a solution of Intermediate(5-bromo-6-methoxy-pyridin-2-yl)dimethyl-amine (78.8 g, 341 mmol) in THF(400 mL) at −70° C. was added a solution of n-butyllithium (2.5 M inhexanes, 127 mL, 317 mmol) dropwise, keeping the internal temperaturebelow −60° C. The purple solution was stirred between −65° C. and −70°C. for 20 min. A solution of ZnCl₂ in 2-methyltetrahydrofuran (1.9 M,167 mL, 317 mmol) was added dropwise to the aryl lithium solution,keeping the internal temperature below −60° C. The resulting mixture wasstirred between −65° C. and −70° C. for 20 min and then warmed to roomtemperature and stirred for 2 h, resulting in a clear pale yellowsolution. The aryl zinc solution was then cannulated into a flaskcontaining Intermediate5-bromo-6-chloro-1-(toluene-4-sulfonyl)-1H-indole-3-carboxylic acidmethyl ester (107.8 g, 244 mmol) anddichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (8.72 g,12.2 mmol) in THF (200 mL). The resulting mixture was stirred at roomtemperature for 2.5 h before quenching with sat. aq. NH₄Cl (800 mL) andextracting with ethyl acetate (1500 mL). The aqueous layer was backextracted with ethyl acetate (750 mL) and the combined organics washedwith brine (1000 mL), dried over MgSO₄, filtered, and concentrated invacuo. The residue was triturated with methanol (˜600 mL) and stirredovernight. The suspension was filtered to give a tan solid. This wasdissolved in hot acetone (2 L) which was partially concentrated to ˜500mL, then slowly cooled and stirred overnight. The resulting solid wasfiltered to yield one crop of desired product (109.1 g). The filtratewas also concentrated to a dark solid which was slurried in acetone,filtered, and the solid dissolved in hot acetone, which was then cooledto yield a second crop (3.3 g) of desired product as an off white solid.(90% total yield). ¹H NMR (DMSO-d₆, 400 MHz) δ=8.51 (s, 1H), 8.11 (d,J=8.6 Hz, 2H), 8.00 (s, 1H), 7.88 (s, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.31(d, J=8.2 Hz, 1H), 6.22 (d, J=8.2 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H),3.06 (s, 6H), 2.37 (s, 3H); MS (ES+) 514.2 (M+H)⁺.

6-chloro-5-(6-dimethylamino-2-methoxy-pyridin-3-yl)-1H-indole-3-carboxylicacid methyl ester

To a solution of Intermediate6-chloro-5-(6-dimethylamino-2-methoxy-pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-indole-3-carboxylicacid methyl ester (109 g, 212 mmol) in THF (1000 mL) at room temperaturewas added tetrabutylammonium fluoride (1.0 M in THF, 400 mL, 400 mmol).The reaction was stirred at reflux for 3 h before cooling to roomtemperature and diluting with ethyl acetate (2000 mL). This was washedwith sat. aq. NaHCO₃ (2×750 mL), sat. aq. NH₄Cl (2×750 mL), water (750mL), and brine (750 mL), and then dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was triturated with methanol (˜500mL) and filtered. The solids were washed with methanol (300 mL) andsuction dried overnight to afford desired product (71.8 g, 94%) as awhite solid. ¹H NMR (DMSO-d₆, 400 MHz) δ=11.99 (s, 1H) 8.13 (s, 1H) 7.82(s, 1H) 7.57 (s, 1H) 7.32 (d, J=8.20 Hz, 1H) 6.22 (d, J=8.20 Hz, 1H)3.78 (s, 3H) 3.76 (s, 3H) 3.07 (s, 6H); MS (ES+) 360.1 (M+H)⁺.

6-chloro-5-[6-(dimethylamino)-2-methoxypyridin-3-yl]-1H-indole-3-carboxylicacid

To a solution of Intermediate6-chloro-5-(6-dimethylamino-2-methoxy-pyridin-3-yl)-1H-indole-3-carboxylicacid methyl ester (45.0 g, 130 mmol) in 1:1 tetrahydrofuran:methanol(1250 mL) at 50° C. was added 2 N NaOH (1250 mL). After 60 h, thereaction was cooled to <5° C. and with stirring, 6 N HCl (417 mL) wasadded dropwise until pH 6-7. The solution was divided in half and eachwas diluted with ethyl acetate (1.5 L) and the layers separated. Theaqueous layers were back extracted with ethyl acetate (2×600 mL). Allorganics were combined and washed with sat. aq. NH₄Cl (1 L) and brine (1L), and dried over MgSO₄, filtered and concentrated in vacuo to givecrude material. Several batches of crude material were combined (117 g)and acetone (3.5 L) was added. This was refluxed to dissolve all solidsand then partially concentrated to ˜1.5 L and slowly cooled to lead tosolids crashing out. These solids were suspended in heptanes (˜500 mL)and stirred at 80° C. for 48 h. Solids were collected by filtration andsuction dried for 15 h to afford desired product (80.0 g) as a solid. ¹HNMR (DMSO-d₆, 400 MHz) δ=12.03 (br. s., 1H) 11.86 (br. s., 1H) 8.04 (d,J=2.73 Hz, 1H) 7.83 (s, 1H) 7.55 (s, 1H) 7.32 (d, J=8.20 Hz, 1H) 6.21(d, J=8.20 Hz, 1H) 3.76 (s, 3H) 3.07 (s, 6H); MS (ES+) 346.1 (M+H)⁺.

Example 1746-chloro-5-[2-methoxy-6-(morpholin-4-yl)pyridin-3-yl]-1H-indole-3-carboxylicacid

Step 1 4-(5-bromo-6-methoxypyridin-2-yl)morpholine

This was prepared in a manner similar to Example 161, step 1 withmorpholine to give the title compound.

Step 26-chloro-5-[2-methoxy-6-(morpholin-4-yl)pyridin-3-yl]-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 161, steps 2-3 with4-(5-bromo-6-methoxypyridin-2-yl)morpholine to give the title compound.MS (ES+) 388.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.05(d, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 7.39 (d, 1H), 6.41 (d, 1H), 3.75(s, 3H), 3.74 (m, 4H), 3.48 (m, 4H).

Example 1756-chloro-5-{2-methoxy-6-[(3R)-3-methoxypyrrolidin-1-yl]pyridin-3-yl}-1H-indole-3-carboxylicacid

Step 1 3-bromo-2-methoxy-6-[(3R)-3-methoxypyrrolidin-1-yl]pyridine

This was prepared in a manner similar to Example 161, step 1 with(S)-3-methoxypyrrolidine to give the title compound.

Step 26-chloro-5-{2-methoxy-6-[(3R)-3-methoxypyrrolidin-1-yl]pyridin-3-yl}-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 161, steps 2-3 with3-bromo-2-methoxy-6-[(3R)-3-methoxypyrrolidin-1-yl]pyridine to give thetitle compound. MS (ES+) 401.8 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 11.90(br. s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.55 (s, 1H), 7.30 (d, 1H),6.04 (d, 1H), 4.08 (m, 1H), 3.75 (s, 3H), 3.53 (m, 2H), 3.41 (m, 2H),3.28 (s, 3H), 2.08 (m, 2H).

Example 1766-chloro-5-{2-methoxy-6-[(3S)-3-methoxypyrrolidin-1-yl]pyridin-3-yl}-1H-indole-3-carboxylicacid

Step 1 3-bromo-2-methoxy-6-[(3S)-3-methoxypyrrolidin-1-yl]pyridine

This was prepared in a manner similar to Example 161, steps 1 with(R)-3-methoxypyrrolidine to give the title compound.

Step 26-chloro-5-{2-methoxy-6-[(3S)-3-methoxypyrrolidin-1-yl]pyridin-3-yl}-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 161, steps 2-3 with3-bromo-2-methoxy-6-[(3S)-3-methoxypyrrolidin-1-yl]pyridine to give thetitle compound. MS (ES+) 401.8 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 11.88(s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.55 (s, 1H), 7.30 (d, 1H), 6.04(d, 1H), 4.09 (m, 1H), 3.75 (s, 3H), 3.53 (m, 2H), 3.41 (m, 2H), 3.28(s, 3H), 2.07 (m, 2H).

Example 177

6-chloro-5-[4-(1-hydroxy-2-methylpropan-2-yl)-3-methoxyphenyl]-N-(methylsulfonyl)-1H-indole-3-carboxamideStep 1 5-bromo-6-chloro-N-(methylsulfonyl)-1H-indole-3-carboxamide

To a mixture of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (445 mg, 1.72mmol), Bis(tert-butylcarbonyloxy)iodobenzene (961 mg, 2.30 mmol) inisopropyl acetate (2 mL) was added methanesulfonamide (111 mg, 1.15mmol). After stirring 5 minutes,Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] (18.3mg, 0.0230 mmol) was added and heated to 50° C. for 2 h. The reactionwas filtered and the collected solid (245 mg) was identified as amixture of the title compound and5-bromo-6-chloro-1H-indole-3-carbaldehyde. The mixture was taken forwardwithout any further purification.

Step 2

A round bottomed flask was charged with a 1:1 mixture of5-bromo-6-chloro-1H-indole-3-carbaldehyde and5-bromo-6-chloro-N-(methylsulfonyl)-1H-indole-3-carboxamide (96 mg, 0.27mmol) as prepared in step 1,2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]-2-methylpropan-1-ol(40 mg, 0.14 mmol) (prepared from2-(4-Bromo-2-methoxyphenyl)-2-methylpropan-1-ol in a manner similar toExample 8, Step 4), potassium carbonate solution (2.0M, 0.27 mL),toluene (0.75 mL), ethanol (0.28 mL), and THF (0.28 mL) then degassedwith nitrogen for 5 minutes. PddppfCl2 was then added and the reactionheated to 110° C. for 3 hours. The reaction was then cooled to rt,diluted with water and ethyl acetate. The layers were separated and theaqueous extracted with ethyl acetate×3. The combined organic layers weredried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude residue was then dissolved in DMSO and purified by reverse phaseHPLC to provide the title compound as an ammonium salt (8.0 mg). MS(ES−): 449.1 (M−H)− HPLC retention time: 1.86 min, Waters XBridge C18, 5μm, 4.6×50 mm, 0.03% NH₄OH, 5-95% acetonitrile in water gradient over4.0 min, hold at 95% acetonitrile in water to 5.0 min, flow 2.0 mL/min.

Examples 178 and 1796-chloro-5-{4-[(2R)-tetrahydro-2H-pyran-2-yl]phenyl}-1H-indole-3-carboxylicacid

6-chloro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid Step 1 Racemic-methyl6-chloro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylate

This was prepared by the method of Example 37, Steps 3, using2-(4-bromophenyl)tetrahydro-2H-pyran ¹H NMR (400 MHz, CDCl₃) δ ppm 8.01(s, 1H), 7.98 (s, 1H), 7.58 (s, 1H) 7.41 (s, 4H) 4.40 (d, 1H), 4.12 (d,1H), 3.86 (s, 3H) 3.68 (t, 1H), 1.92 (m, 2H) 1.71 (m, 4H)

Step 2 Methyl6-chloro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylate

Racemic methyl6-chloro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylatewas subjected to preparative chiral SFC. Column: Chiralpak AD-H 250×4.6mm I.D., 5 um Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%Flow rate: 2.35 mL/min Wavelength: 220 nm. Peak 1 was isolated asIsomer 1. Retention time=8.928 minutes; Column: Chiralpak AD-H 250×4.6mm I.D., 5 um Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%Flow rate: 2.35 mL/min Wavelength: 220 nm, ¹H NMR (400 MHz, CDCl₃) δ ppm8.11 (s, 1H), 7.95 (d, 1H), 7.54 (s, 1H) 7.47 (d, 2H) 7.43 (d, 2H) 4.40(d, 1H), 4.18 (d, 1H), 3.90 (s, 3H) 3.66 (t, 1H), 1.92 (m, 2H) 1.71 (m,4H). Peak 2 was isolated as Isomer 2. Retention time=9.311 minutes;Column: Chiralpak AD-H 250×4.6 mm I.D., 5 um Mobile phase: methanol(0.05% DEA) in CO2 from 5% to 40% Flow rate: 2.35 mL/min Wavelength: 220nm

¹H NMR (400 MHz, CDCl₃)) δ ppm 8.11 (s, 1H), 7.95 (d, 1H), 7.54 (s, 1H)7.47 (d, 2H) 7.43 (d, 2H) 4.40 (d, 1H), 4.18 (d, 1H), 3.90 (s, 3H) 3.66(t, 1H), 1.92 (m, 2H) 1.71 (m, 4H)

Step 36-chloro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid Isomer 1

This was prepared by the method of Example 37, Steps 4, using methyl6-chloro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylateIsomer 1 from step 2 to give the title compound Example 178. Retentiontime=7.119 Column: IC 250*4.6 mm I.D., 5 um. Mobile phase: ethanol(0.05% DEA) in CO2 from 5% to 40%. Flow rate: 2.35 mL/min Wavelength:220 nm. MS (ES+) 337.9 (M−H₂O)⁺¹H NMR (400 MHz, CD3OD) δ ppm 8.05 (s,1H), 7.96 (s, 1H), 7.56 (s, 1H) 7.41 (s, 4H) 4.43 (d, 1H), 4.12 (d, 1H),3.68 (m, 1H) 1.94 (m, 2H), 1.70 (m, 4H).

6-chloro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylicacid Isomer 2

This was prepared by the method of Example 37, Steps 4, using methyl6-chloro-5-[4-(tetrahydro-2H-pyran-2-yl)phenyl]-1H-indole-3-carboxylateIsomer 2 from step 2 to give the title compound Example 179. Retentiontime=7.343 Column: IC 250*4.6 mm I.D., 5 um. Mobile phase: ethanol(0.05% DEA) in CO2 from 5% to 40%. Flow rate: 2.35 mL/min Wavelength:220 nm. MS (ES+) 337.9 (M−H₂O)⁺¹H NMR (400 MHz, CD3OD)) δ ppm 8.03 (s,1H), 7.97 (s, 1H), 7.57 (s, 1H) 7.41 (s, 4H) 4.43 (d, 1H), 4.12 (d, 1H),3.68 (m, 1H) 1.94 (m, 2H), 1.70 (m, 4H).

Example 1806-chloro-5-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid

Step 1 1-[2-(4-bromophenoxy)ethyl]-1H-pyrazole

The mixture of 1-bromo-4-(2-bromoethoxy)benzene (1.00 g, 3.57 mmol),pyrazole (0.360 g, 5.36 mmol) and cesium carbonate (1.75 g, 5.36 mmol)in acetonitrile (10 mL) was heated at 80° C. and stirred for 2 hours.The reaction mixture was filtered. The filtrate was concentrated invacuo to give a white solid, which was purified by silica gelchromatography to give the title compound (1.0 g, 100%) as a whitesolid. 1H NMR (400 MHz, CDCl3) δ ppm 7.56 (d, 1H) 7.54 (d, 1H) 7.35 (d,2H), 6.74 (d, 2H), 6.26 (m, 1H), 4.53 (t, 2H), 4.30 (t, 2H).

Step 26-chloro-5-{4-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid

This was performed in a manner similar to Example 37, Steps 3-4 using1-[2-(4-bromophenoxy)ethyl]-1H-pyrazole to give 52 mg of the titlecompound. MS (ES+): 382.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.13(s, 1H) 11.95 (br. s, 1H) 8.08 (s, 1H) 7.93 (s, 1H) 7.83 (m, 1H), 7.62(s, 1H) 7.49 (m, 1H) 7.35 (d, 2H), 7.01 (d, 2H), 6.27 (m, 1H), 4.53 (t,2H), 4.40 (t, 2H).

Example 1816-chloro-5-[4-(2-methoxyethoxy)phenyl]-1H-indole-3-carboxylic acid

Step 1 1-bromo-4-(2-methoxyethoxy)benzene

Potassium carbonate (2.4 g, 17.3 mmol) was suspended in N,N-dimethylformamide (15 mL). 4-bromophenol (1.00 g, 5.78 mmol) and1-bromo-2-methoxyethane (0.964 g, 6.94 mmol) were added into thereaction sequentially and the resulting mixture was stirred at 60° C.for 17 hours. The reaction mixture was diluted with water and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith brine (50 mL) dried over sodium sulfate and evaporated to give thetitle compound (1.3 g, 99%) as a yellow oil.

Step 2 6-chloro-5-[4-(2-methoxyethoxy)phenyl]-1H-indole-3-carboxylicacid

This was performed in a manner similar to Example 37, Steps 3-4 using1-bromo-4-(2-methoxyethoxy)benzene to give 108 mg of the title compound.MS (ES+): 345.9 (M+H). ¹H NMR (400 MHz, METHANOL-d₄) ppm 8.03 (s, 1H)8.01 (s, 1H) 7.58 (s, 1H) 7.38 (d, 2H) 7.02 (d, 2H) 4.19 (m, 2H)3.73-3.85 (m, 2H) 3.47 (s, 3H).

Example 182

6-chloro-5-[4-(oxetan-2-ylmethoxy)phenyl]-1H-indole-3-carboxylic acidStep 14,4,5,5-tetramethyl-2-{4-[(3-methyloxetan-3-yl)methoxy]phenyl}-1,3,2-dioxaborolane

A vial was charged with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (220 mg, 1.00mmol), (3-methyloxetan-3-yl)methanol (122 mg, 1.20 mmol),triphenylphosphine (353 mg, 1.50 mmol) and tetrahydrofuran (2 mL). Themixture was stirred at 30° C. for 15 min under nitrogen atmosphere. Tothe mixture was added Diisopropyl azodicarboxylate (300 mg, 1.50 mmol).The mixture was purged with nitrogen and heated to 50° C. for 17 hrs.The mixture was diluted with ethyl acetate and washed with brine. Theorganic layer was dried (sodium sulfate) and concentrated to give crudeproduct (900 mg) as yellow gum, which was purified through flash columnchromatography to give the title compound (263 mg, 87%) as white solid.

Step 2 6-chloro-5-[4-(oxetan-2-ylmethoxy)phenyl]-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 43, Step 1-2 with4,4,5,5-tetramethyl-2-{4-[(3-methyloxetan-3-yl)methoxy]phenyl}-1,3,2-dioxaborolaneto give 8.5 mg of the title compound. MS (ES+): 380.1 (M+Na)¹H NMR (400MHz, DMSO-d₆) ppm 11.95 (br. s, 1H), 8.08 (d, 1H), 7.93 (s, 1H), 7.64(s, 1H), 7.36 (d, 2H), 7.06 (d, 2H), 5.05 (m, 1H), 4.47-4.60 (m, 2H),4.11-4.26 (m, 2H) 2.67-2.78 (m, 1H) 2.53-2.62 (m, 1H).

Example 1836-chloro-5-{4-[(1-hydroxypropan-2-yl)oxy]phenyl}-1H-indole-3-carboxylicacid

Step 1 1-(trityloxy)propan-2-yl methanesulfonate

To a solution of propane-1,2-diol (4.00 g, 52.0 mmol) in drydichloromethane (50 mL) at 0° C. was added trityl chloride (15 g, 0.052mol), N,N-dimethylaminopyridine (0.82 g, 6.8 mmol) and triethylamine(13.13 g, 1.33 mmol). The resulting mixture was stirred at roomtemperature for 14 hours. Methanesulfonyl chloride (6.36 g, 56.0 mmol)slowly at 0° C. Then the reaction was stirred at room temperature for 2hours. The reaction mixture was diluted with water (100 mL) andextracted with dichloromethane (100 mL*3). The organic layer was washedwith water (100 mL), and 1 N hydrochloric acid (100 mL*2). The combinedorganic layers were dried over sodium sulfate and concentrated to give acrude product, which was purified on silica gel column (petroleum ether:ethyl acetate=8:1 to 10:1) to give the title compound (15 g) as aviscous oil, which was used in the next step without furtherpurification.

Step 2 1-iodo-4-{[1-(trityloxy)propan-2-yl]oxy}benzene

To a solution of potassium carbonate (0.63 g, 4.5 mmol) indimethylformaide (10 mL) was purged with nitrogen for 10 min at 75° C.4-iodophenol (0.55 g, 2.5 mmol) was added to the mixture and thesolution was purged with nitrogen for additional 10 min. To the reactionmixture 1-(trityloxy)propan-2-yl methanesulfonate (1.00 g, 2.53 mmol)was added and stirred for 24 hours at the same temperature. The reactionmixture was diluted with water (20 mL) and extracted with ethyl acetate(20 mL*3). The combined organic layer was dried over sodium sulfate andconcentrated. The crude product was purified by combiflash silica gelchromatography (petroleum ether:ethyl acetate=10:1) to give the titlecompound (600 mg, 46%) as colorless oil.

Step 3 2-(4-iodophenoxy)propan-1-ol

To a solution of 1-iodo-4-{[1-(trityloxy)propan-2-yl]oxy}benzene (350mg, 0.67 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid(5 mL). The mixture was stirred at room temperature for 4 hours. Thereaction mixture was concentrated and purified by combiflash (petroleumether:ethyl acetate=10:1 to 4:1) to give the title compound (100 mg,55%) as a white solid, which was used into next step directly. ¹H NMR(400 MHz, CDCl3) ppm 7.55 (d, 2H), 6.72 (d, 2H), 4.45 (m, 1H), 3.70 (m,2H), 1.96 (t, 1H), 1.25 (d, 3H).

Step 46-chloro-5-{4-[(1-hydroxypropan-2-yl)oxy]phenyl}-1H-indole-3-carboxylicacid

This was performed in a manner similar to Example 37, Steps 3-4 using2-(4-iodophenoxy)propan-1-ol to give 24 mg of the title compound. MS(ES+): 368.1 (M+Na).

¹H NMR (400 MHz, DMSO-d₆) ppm 11.54 (br. s, 1H) 8.18 (br. s., 1H) 7.87(s, 1H) 7.53 (s, 1H) 7.31 (d, 2H) 6.99 (d, 2H) 4.92 (br. s., 1H)4.41-4.52 (m, 1H) 3.45-3.65 (m, 2H) 1.25 (d, 3H).

Example 1846-chloro-5-{6-[(3S)-3-hydroxypyrrolidin-1-yl]-2-methoxypyridin-3-yl}-1H-indole-3-carboxylicacid

Step 1 (3S)-1-(6-methoxypyridin-2-yl)pyrrolidin-3-ol

To a solution of 2-chloro-6-methoxypyridine (1.966 g, 3.750 mmol) andcommercially available (3S)-pyrrolidin-3-ol (1.437 g, 16.50 mmol) intetrahydrofuran/methanol (137 mL/6.7 mL), was added Pd₂(dba)₃ (62.2 mg,0.0688 mmol), BippyPhos (139.2 mg, 0.2750 mmol) and potassium hydroxide(1.16 g, 20.6 mmol, 88% pellets). The reaction was then was purged withnitrogen for 2 minutes and stirred at 70° C. for 18 hours. The reactionwas filtered, quenched with saturated ammonium chloride solution,adjusted to pH=7˜8 with 1N hydrochloric acid and extracted withdichloromethane (100 mL*2) and ethyl acetate (100 mL*3). The combinedorganic phase was washed with saturated brine, dried over sodium sulfateand evaporated in vacuo. The residue was then purified by silica gelchromatography with ethyl acetate/petroleum ether, 0-25% to give thetitle compound (1.65 g, 62%) as a yellow gum that was used withoutfurther purification.

Step 2 (3S)-1-(5-bromo-6-methoxypyridin-2-yl)pyrrolidin-3-ol

To a solution of (3S)-1-(6-methoxypyridin-2-yl)pyrrolidin-3-ol (1.6 g,8.24 mmol) in chloroform (90 mL), was added N-bromosuccinimide (1.47 g,8.24 mmol) at 0° C. with an ice bath. The reaction was allowed to stirat room temperature (8° C.) for 5 hour. TLC (petroleum ether/ethylacetate) showed that the reaction was complete. The reaction mixture wasevaporated to remove chloroform, dissolved in DCM (20 mL) and dilutedwith water (15 mL). The resulting mixture was separated and the aqueousphase was extracted with dichloromethane (25 mL*3). The combined organicphase was washed with brine, dried over sodium sulfate and evaporated invacuo. The residue was purified by silica gel chromatography with ethylacetate/petroleum ether, 0-25% to give the title compound (187 mg, 8.5%)as a yellow gum. ¹H NMR (400 MHz, CDCl3) ppm 7.46 (d, 1H) 5.77 (d, 1H)4.44-4.59 (m, 1H) 3.92 (s, 3H) 3.37-3.61 (m, 4H) 1.96-2.24 (m, 3H).

Step 36-chloro-5-{6-[(3S)-3-hydroxypyrrolidin-1-yl]-2-methoxypyridin-3-yl}-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 161, steps 2-3 with(3S)-1-(5-bromo-6-methoxypyridin-2-yl)pyrrolidin-3-ol to give 30.3 mg ofthe title compound. MS (ES+) 387.9 (M+H)⁺. ¹H NMR (400 MHz, CD3OD) ppm11.44 (br. s, 1H) 7.98 (s, 1H) 7.94 (s, 1H) 7.54 (s, 1H) 7.30 (d, 1H)6.06 (d, 1H) 4.51-4.59 (m, 1H) 3.85 (s, 3H) 3.50-3.72 (m, 4H) 2.13-2.25(m, 1H) 2.00-2.12 (m, 1H). Retention Time: 1.829 Column: Chiralpak AD-350*4.6 mm I.D., 3 um in; Mobile phase: iso-propanol (0.05% DEA) in CO2from 5% to 40%; Flow rate: 4 mL/min Wavelength: 220 nm.

Example 1856-chloro-5-{6-[(3R)-3-hydroxypyrrolidin-1-yl]-2-methoxypyridin-3-yl}-1H-indole-3-carboxylicacid

This was prepared in a manner similar to Example 184, using(3R)-pyrrolidin-3-ol as the starting material to provide 39.2 mg of thetitle compound. MS (ES+) 387.9 (M+H)⁺. ¹H NMR (400 MHz, CD3OD) ppm 11.43(br. s, 1H) 7.98 (s, 1H) 7.94 (s, 1H) 7.53 (s, 1H) 7.31 (d, 1H) 6.05 (d,1H) 4.52-4.58 (m, 1H) 3.86 (s, 3H) 3.50-3.71 (m, 4H) 2.12-2.24 (m, 1H)2.00-2.11 (m, 1H). Retention Time: 1.999 Column: Chiralpak AD-3 50*4.6mm I.D., 3 um in; Mobile phase: iso-propanol (0.05% DEA) in CO2 from 5%to 40%; Flow rate: 4 mL/min Wavelength: 220 nm.

Example 1866-chloro-5-{6-[(2-hydroxyethyl)(methyl)amino]-2-methoxypyridin-3-yl}-1H-indole-3-carboxylicacid

This was prepared by the method of Example 161, Steps 1-3, using2-(methylamino)ethanol to give the title compound. MS: (ES+): 375.9(M+H)+. 1H NMR (400 MHz, DMSO-d6) ppm 11.86 (br s, 1H), 8.03 (s, 1H),7.83 (s, 1H), 7.55 (s, 1H), 7.30 (d, 1H), 6.19 (d, 1H), 4.69 (br s, 1H),3.74 (s, 3H), 3.61 (br s, 4H), 3.08 (s, 3H).

Example 1876-chloro-5-{4-[3-(4-methoxypiperidin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylicacid

This was prepared by the method of Example 180, Steps 1-2, using4-methoxypiperidine and 1-bromo-4-(3-bromopropoxy)benzene to give thetitle compound. MS (ES+): 443.2 (M+H)+1H NMR (400 MHz, DMSO-d6) ppm11.94 (br s, 1H), 8.20 (br s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.61 (s,1H), 7.33 (d, 2H), 7.00 (d, 2H), 4.04 (t, 2H), 3.22 (s, 3H), 3.17 (m,1H), 2.70 (m, 2H), 2.45 (m, 2H), 2.10 (m, 2H), 1.89 (m, 2H), 1.84 (m,2H), 1.42 (m, 2H).

Example 1886-chloro-5-{4-[3-(4-methyl-3-oxopiperazin-1-yl)propoxy]phenyl}-1H-indole-3-carboxylicacid

This was prepared by the method of Example 180, Steps 1-2, using1-methylpiperazin-2-one and 1-bromo-4-(3-bromopropoxy)benzene to givethe title compound. MS (ES+): 441.9 (M+H)+. 1H NMR (400 mHz, DMSO-d6)ppm 11.90 (br s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 7.33 (d,2H), 7.00 (d, 2H), 4.05 (t, 2H), 3.27 (m, 4H), 3.00 (s, 2H), 2.81 (s,3H), 2.66 (m, 2H), 1.92 (quint, 2H).

Example 1896-chloro-5-(4-{3-[(3R)-3-fluoropyrrolidin-1-yl]propoxy}phenyl)-1H-indole-3-carboxylicacid

This was prepared by the method of Example 180, Steps 1-2, using(R)-3-fluoropyrrolidine and 1-bromo-4-(3-bromopropoxy)benzene to givethe title compound. MS (ES+): 416.9 (M+H)+. 1H NMR (400 mHz, DMSO-d6)ppm 11.91 (br s, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.61 (s, 1H), 7.34 (d,2H), 7.00 (d, 2H), 5.19 (m, 1H), 4.06 (t, 2H), 2.82 (m, 2H), 2.65 (m,1H), 2.58 (m, 2H), 2.31 (m, 1H), 2.13 (m, 1H), 1.91 (m, 2H), 1.83 (m,1H).

Example 1904,6-difluoro-5-{4-[2-(tetrahydrofuran-3-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid

Step 14,4,5,5-tetramethyl-2-(4-(2-(tetrahydrofuran-3-yl)ethoxy)phenyl)-1,3,2-dioxaborolane

This was prepared by the method of Example 182, Step 1 using2-(tetrahydrofuran-3-yl)ethanol to give the title compound.

Step 24,6-difluoro-5-{4-[2-(tetrahydrofuran-3-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid

This was prepared by the method of Example 167, Steps 2-3 using4,4,5,5-tetramethyl-2-(4-(2-(tetrahydrofuran-3-yl)ethoxy)phenyl)-1,3,2-dioxaborolaneto give the title compound. MS(APCI+): 388.1 (M+H)+. 1H NMR (300 mHz,DMSO-d6) ppm 12.12 (br s, 1H), 11.98 (br s, 1H), 8.06 (s, 1H), 7.35 (d,2H), 7.23 (d, 1H), 7.04 (d, 2H), 4.06 (m, 2H), 3.85 (m, 1H), 3.75 (m,1H), 3.64 (m, 1H), 3.33 (m, 1H, obscured by water peak), 2.33 (m, 1H),2.05 (m, 1H), 1.83 (m, 2H), 1.56 (m, 1H)

Example 1914,6-difluoro-5-{4-[2-(tetrahydrofuran-2-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid

Step 14,4,5,5-tetramethyl-2-(4-(2-(tetrahydrofuran-2-yl)ethoxy)phenyl)-1,3,2-dioxaborolane

This was prepared by the method of Example 182 Step 1 using2-(tetrahydrofuran-2-yl)ethanol to give the title compound.

Step 24,6-difluoro-5-{4-[2-(tetrahydrofuran-2-yl)ethoxy]phenyl}-1H-indole-3-carboxylicacid

This was prepared in a similar method to Example 167, Steps 2-3 using4,4,5,5-tetramethyl-2-(4-(2-(tetrahydrofuran-2-yl)ethoxy)phenyl)-1,3,2-dioxaborolaneto give the title compound. MS(APCI+): 388.1 (M+H)+. 1H NMR (300 mHz,DMSO-d6) ppm 12.12 (br s, 1H), 11.98 (br s, 1H), 8.05 (s, 1H), 7.35 (d,2H), 7.23 (d, 1H), 7.04 (d, 2H), 4.10 (t, 2H), 3.94 (m, 1H), 3.78 (m,1H), 3.61 (m, 1H), 2.08-1.81 (m, 5H), 1.50 (m, 1H)

AMPK In Vitro Biochemical Assay Expression and Purification of AMPK

We designed a tricistronic AMPK expression construct that included openreading frames encoding the full-length γ₁, β₁ and α₁ subunits of humanAMPK with a ribosome-binding site (RBS) ahead of each coding region andsubcloned this into pET-14b expression vector (Novagen, Madison, Wis.)using standard molecular biology techniques. AMPK tricistronic constructwas transformed into E. coli BL21-CodonPlus™ (DE3)-RIPL strain(Stratagene) and transformants were selected on LB (Luria-Bertani) agarplates containing ampicillin (100 μg/ml). Ten liters of LB medium (MPBiomedical LB broth #11-3002-032) containing 100 ug/ml carbenicillin wasinoculated with 100 ml E. coli shake flask culture (BL-21, pET-14b, AMPK111) in a BF4 10 L working volume bioreactor (New Brunswick ScientificCo.) at 37° C., 600 rpm, 6 L/minute aeration. Optical density samplemeasurements were made on an UltroSpec 2000 spectrophotometer (PharmaciaBiotech) at 600 nm. When the cell density reached ˜0.9 OD, thetemperature was reduced to 18° C. and the culture was induced at 18° C.with 0.1 mM Isopropylthiogalactoside (IPTG). The cell paste wascollected at ˜18 hours post induction by refrigerated continuous flowcentrifugation (Heraeus, rotor #8575) at 15,000 rpm at 4° C. The cellpellets were aliquoted into four portions, flash frozen in liquidnitrogen and were stored at −80° C. until purification. Forpurification, frozen cell paste was thawed and resuspended in 50 mllysis buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10% glycerol, 2 mMTris-2-carboxyethyl phosphine (TCEP), 20 mM imidazole and 0.001% TritonX-100). After sonication, insoluble material was removed bycentrifugation at 15,000 rpm in a Sorvall® RC5 plus centrifuge for 30min at 4° C. and the supernatant was loaded onto a 5 ml HisTrap™ HPcolumn (GE Healthcare, Piscataway, N.J.) and washed with five columnvolumes of lysis buffer. Bound proteins were eluted using an elutionbuffer containing 300 mM imidazole. Fractions containing AMPK subunitswere pooled based on SDS-10% PAGE analysis and dialyzed overnight indialysis buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10% glycerol, 2 mMTCEP, and 0.001% Triton X-100). The purified AMPK was phosphorylated onits activation loop Thr 172 by incubating 1.0 μM AMPK complex in thepresence of 200 nM CaMKKβ (calmodulin-dependent protein kinase kinase βobtained from the University of Dundee) in phosphorylation buffer for 30min at 30° C. The phosphorylated AMPK complex was re-purified onHisTrap™ HP column as before, dialyzed over night in dialysis buffer.The phosphorylated AMPK complex was further purified by gel filtrationchromatography with a Superdex 200 HiLoad 16/60 column (GE Healthcare)in SEC buffer (50 mM Tris, pH 8.0, 150 mM NaCl, 10% glycerol, 2 mM TCEP,and 0.001% Triton X-100). The final samples were stored at −20° C. with25% glycerol.

Expression and Purification of PP2A

We cloned human recombinant Protein Phosphatase 2A catalytic subunit(PP2A C; 309 aa, NM_(—)004156.2) into pFastBac HT-A expression vectorand expressed in insect cells (Sf9) with a N-terminal 10×-His Tag. TheSf9 cells were cultured in SF-900-III SFM medium (Invitrogen #12658-027)in a Wave cellbag disposable bioreactor (GE Healthcare #CB0050L10-02) at27° C. under 0.3 L/min aeration. 2×1 ml aliquots of baculovirus infectedinsect cells (BIIC1) were removed from −80° C. preservation, rapidlythawed and used to infect 20 liters of log phase Sf-9 cells at a viablecell density ˜1.5×106 vc/ml at >95% viability. The harvest time (72hours post infection) was indicated by percent cell viability (to85-90%) and increased cell diameter (3-4 μm). The cell paste wascollected by refrigerated continuous flow centrifugation at 3500×g(Heraeus/Thermo Scientific model Contifuge 28rs and #8575 rotor),aliquoted, flash frozen in liquid nitrogen and stored at −80° C. Forpurification, the cell paste was resuspended in 500 mL lysis buffer (50mM Tris pH 8.0, 150 mM NaCl, 25 mM imidazole, 10% glycerol, 2 mM MgCl2,2 mM TCEP+protease inhibitor cocktail. After lysis, cellular debris wasremoved by centrifugation at 36K×g for 1 hour. The resulting supernatantwas filtered at 0.2 micron before applying to a 1 mL nickel charged IMACcolumn (HisTrap, GE). The bound resin was washed to baseline with 50 CVof 50 mM Tris pH 8.0, 150 mM NaCl, 25 mM imidazole, 10% glycerol, 2 mMMgCl2, 2 mM TCEP before eluting over a 20 CV gradient to 100% with washbuffer containing 500 mM imidazole. Pooled fractions containing PP2Awere combined and diluted 10× with 50 mM Tris pH 8.0, 10% glycerol, 1 mMTCEP and applied to a 1 mL AIEX resin (HiTrap QFF, GE). The bound resinwas washed with dilution buffer and PP2A was eluted over a 20 CVgradient to 100% 50 mM Tris pH 8.0, 500 mM NaCl, 10% glycerol, 1 mM TCEPand was further diluted 1:1 with 50 mM Tris pH 8.0, 150 mM NaCl, 10%glycerol, and 1 mM TCEP buffer.

Biochemical Profiling of AMPK Activators by

The biochemical EC₅₀ (half-maximal concentration required for fullactivation) of compounds for the activation of AMPK was evaluated by³³P-based assay using SAMS peptide (commercially available) derived fromACC-1. Twenty μl of phosphorylated AMPK diluted in assay buffer, (50 mMHEPES, 1 mM EGTA, 10 mM MgCl2, 0.25 mM DTT, 0.01% Tween-20, 0.01% BSA(pH 7.5)) was added to 384 well plates containing 1 μL of test compound.Following a fifteen minute room temperature incubation, 10 μL of proteinphosphatase PP2A was added to the plate to dephosphorylate pThr172 ofAMPK. After incubation for 90 minutes, 10 μL of substrate mixturecontaining 41 nM okadaic acid, 82 μM SAMS peptide, 82 μM ATP and traceramounts (6.8 nM) of ³³P-containing ATP was added to the plate. Thereaction was terminated after 60 minutes incubation at room temperatureby the addition of 15 μL of 2% H₃PO₄. Subsequently, 45 μl of reactionmix was transferred to 384 well Millipore MZPH filter plates (MZPHNO50)pre-treated with 25 μL of 2% H₃PO₄ and the plates were washed threetimes with assay buffer. 20 μL of Ready Safe scintillation fluid wasadded to dried plates followed by detection on the Trilux detector.Counts from basal wells (enzyme, diluent, PP2A and substrate) weresubtracted from each well. Counts were expressed as a % of positivecontrol wells (enzyme, allosteric activator or AMP, PP2A and substrate).EC₅₀ values were determined from this data using a 4-parameter fitalgorithm and are presented in Table 1.

TABLE 1 Example EC₅₀ Maximum Number nM n %  1 4.2 3 83  2 64.7 1 88  3458.6 3 82  4 71.0 3 62  5 35.7 2 78  6 17.3 1 61  7 671.3 3 78  8 219.71 94  9 71.2 3 81  10 69.9 3 91  11 554.1 3 73  12 42.5 1 82  13 6.9 173  14 150.5 1 100  14A 100.7 1 101  14B 118.2 1 91  15 631.9 3 92  16412.3 3 114  17 125.8 1 107  18 181.5 2 92  19 383.3 2 96  20 53.6 1 62 21 93.5 3 86  22 13.7 2 122  23 16.0 1 88  24 252.3 3 91  25 111.1 2 78 26 124.5 3 74  27 36.9 2 107  28 1077 3 98  29 382.9 2 101  30 30.0 392  31 130 3 104  32 570.2 1 97  33 85.3 5 83  34 315.3 1 122  35 74.2 472  36 7.1 1 70  37 247.8 1 81  38 106.2 1 93  39 11.1 1 75  40 821 3 78 41 9.6 1 62  42 21.8 3 65  43 1.7 1 68  44 85.0 1 78  45 224.8 3 94  4765.3 3 96  48 110.5 3 89  50 203.8 2 79  51 320.2 2 93  52 38.1 3 91  5322.0 2 120  54 32.5 1 74  55 209 2 87  56 333.5 2 137  57 64.5 3 107  5889.2 1 107  59 133 1 75  60 7.8 4 65  61 2.3 1 57  62 33.3 1 74  63432.5 3 89  64 169.4 3 82  65 134.6 3 103  66 26.9 4 98  67 2.4 1 112 68 4.3 1 117  69 263.6 1 74  70 77.5 1 106  71 14.0 1 75  72 4.3 1 107 73 790.1 3 118  74 44.3 1 110  75 0.5 1 91  76 271.1 1 104  77 207 3 89 78 1995 3 68  79 103.9 3 102  80 181.9 2 108  81 182.5 3 97  82 215.7 386  83 819 3 108  84 343.6 3 72  86 99.2 3 99  87 69.5 3 112  88 58.1 278  89 65.4 3 99  90 372.3 2 120  91 695.4 3 101  94 17.9 1 92  95 830.42 91  96 58.1 3 83  97 202 4 94  98 1045 2 83  99 38.5 3 94 100 189.6 280 101 1.8 3 61 102 33.7 3 79 103 8.3 2 80 104 36.5 3 88 105 122.3 1 84106 73.0 2 94 107 43.5 2 60 108 94.4 2 92 109 82.3 2 94 110 205.8 1 90111 174.6 3 12 112 1316 1 80 113 344.5 3 100 114 36.8 2 94 115 27.0 2 95116 47.8 2 104 117 90.2 2 107 118 169.1 1 125 119 44.8 2 97 120 52.4 288 121 369.2 3 102 122 160.3 2 75 123 100.4 1 57 124 93.8 2 93 125 132.52 90 126 26.8 2 110 127 17.2 1 81 128 19.8 3 70 130 304.8 3 100 131 17.92 95 132 482.7 1 46 133 >50000 2 134 82.8 1 16 135 6.5 4 82 136 39.3 2100 138 40.4 1 117 139 72.8 3 84 141 9.3 2 119 142 21.5 3 92.9 143 17.672 193.8 144 236.3 1 118.7 145 57.91 2 65.15 146 35.26 1 119 147 10.14 1131.5 148 6.56 1 119.1 149 76.92 2 88.86 150 165 1 111.7 151 37.82 1103.8 152 16.75 1 111.6 153 136.9 1 112.3 154 28.31 1 104.8 155 47.79 1126.9 156 31.9 3 98.88 157 50.12 3 96.1 158 125 1 146.1 159 47.83 198.63 160 17.3 1 118.3 161 8.328 2 92.94 162 192 1 123 163 12.9 2 110163 10.31 1 112.4 164 17.51 1 141.6 165 31.9 1 159.2 166 129.4 2 107.1167 9.33 2 143.1 168 170.7 4 108.6 169 7.063 1 116 170 33.95 1 100.2 17132.9 2 69.2 172 10.96 1 101.1 173 11.7 5 115 174 15.3 3 49.4 175 22.6 378.2 176 5.6 2 62.4 177 62.3 2 110.9 178 2.602 1 74.92 179 14.21 1 90.21180 11.6 3 76.2 181 16.9 2 81.4 182 19 1 80 183 28.1 2 87.3 184 6.2 1 84185 2.9 1 106 186 84.5 4 114 187 61.4 4 105 188 52.7 4 129 189 57.7 4112 190 109.1 4 108 191 120.6 3 140

Human Podocyte Assay

Conditionally immortalized human podocytes were seeded at a density of10⁴ cells/well onto a collagen I coated 24 well plate and allowed todifferentiate at 37° C. for 7-10 days in glucose free RPMI with 10% FBSand the medium was replaced with fresh medium every other day. Upondifferentiation, the cells were treated with the test compounds (1 mMAICAR and Ex 1) in serum free RPMI with 30 mM glucose. The medium in thenegative control wells was replaced with glucose free RPMI containing0.2% serum and the medium in positive control wells was replaced withserum free RPMI containing 30 mM glucose and DMSO. After 48 hours,apoptotic cell death was assessed using Cell Death ELISA (Roche, Inc)according to the manufacturer's instructions. Briefly, podocytes werelysed in lysis buffer provided in the kit, followed by centrifugationfor 10 min at 200×G. 20 μl of the supernatant were added tostreptavidin-coated microtiter plates followed by incubation withAnti-histone biotin and anti-DNA peroxidase-labeled antibodies for 2hrs. After incubation and washing, color was developed using theprovided substrate to the wells. Absorbance was measured at 405 nm.Parallel cells were lysed with Cell Lysis Buffer (Cell SignalingTechnology), separated on 4-12% gradient SDS-PAGE gels (Invitrogen),transferred to nitrocellulose membrane, and probed using antibodiesspecific to phospho-T172 AMPK alpha, total AMPK alpha, phospho-79Acetyl-CoA-Carboxylase, and total Acetyl-CoA-Carboxylase.

1. (canceled)
 2. A compound of structure

or a pharmaceutically acceptable salt thereof. 3-5. (canceled)
 6. Acompound of structure

or a pharmaceutically acceptable salt thereof.
 7. A compound ofstructure

or a pharmaceutically acceptable salt thereof.
 8. A compound ofstructure

or a pharmaceutically acceptable salt thereof.
 9. A compound ofstructure

or a pharmaceutically acceptable salt thereof.
 10. A compound ofstructure

or a pharmaceutically acceptable salt thereof.